Biodegradable polymer blend

Abstract

The present invention relates to a biodegradable polymer blend suitable for use in the fabrication of an orthopaedic fixation implant. The invention also relates to an implant (e.g., an orthopaedic fixation implant) comprising the polymer blend, as well as to a method of forming the polymer blend and the implant.

Description

Biodegradable Polymer Blend

[0001] This invention relates to a polymer blend. The blend is both strong and degrades slowly under biological conditions and is particularly useful in orthopaedic fixation implants.BACKGROUND

[0002] Orthopaedic procedures are seemingly ever increasing due to both an increase in the aging population and a rise in obesity rates, contributing to the increase in bone fractures.Permanent fixation implants are expected to serve for the whole term of a patient’s life, in contrast to temporary fixation implants, which are required fora shorter time period to allow for the healing of broken bones. Current orthopaedic fixation implants of both categories are typically produced from metallic materials, which display adequate mechanical properties and fatigue and corrosion resistance; however, the stiffness of metallic materials is greater than that of bone, and this can cause stress shielding. As a less stiff alternative to metal fixation implants, aliphatic polyesters are a group of biocompatible and bioresorbable polymers used in a wide range of biomedical applications. Some of the most commonly studied polymers include polylactide (PLA), polycaprolactone (PCL) and polyhydroxyalkanoates (PHA).

[0003] Each of these polymers has advantages and disadvantages for biomedical applications. Poly(L-lactic acid) (PLLA) has been used in a range of medical devices, including various orthopaedic clinical applications, where its favourable mechanical properties when compared to other biopolymers offers a performance advantage. PLLA has a high tensile strength, low ductility and is a semi-crystalline polymer. The crystalline structure can make PLLA mechanically superior when compared to other polyesters in load-bearing applications. PLLA has glass transition and melting temperatures of 55-80 °C and 170-180 °C, respectively. In contrast, polycaprolactone (PCL) is a soft, semi-crystalline polymer with a low melting and glass transition temperatures (55-60 °C and -54 °C, respectively). Although it possesses high ductility (with a tensile elongation at break of over 700%) and a high impact strength, it has a low tensile strength (~23 MPa) and Young’s modulus. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) is an aliphatic biodegradable polyester with a melting temperature between 80 and 160 °C and a glass transition temperature in the range of -5 to 20 °C depending on the HV (hydroxyvalerate) content of the copolymer, which can be adjusted to control the mechanical properties of the polymer. PHBV has been shown to produce consistent favourable bone tissue adaptation response in addition to the elimination of any undesirable chronic inflammatory responses (up to 12 months after fixation implantation).

[0004] Both PLLA and PHBV are hard polymers with poor impact performance, which limits their use. The brittle nature of the polymers can be improved through blending with soft ductile polymers. Blending of polymers is a simple yet effective method to obtain new materials with enhanced properties, as the limitations of the dominant component in the blend can be mitigated. Tuning of the physical and mechanical properties of a blend can be achieved with the selection of appropriate materials, adjustment of the blend compositions and appropriate preparation conditions. The blending of PLA / PCL and PLA / PHBV as two co-polymer blends for use in biomedical applications has been previously investigated. These studies have shown that it is possible to increase the fracture toughness or elongation at break of PLLA by blending with PCL or PHBV, but with reduced modulus or tensile strength.

[0005] R. Naseem, et al., Molecules, 2022, 27, 7633 discloses a ternary polymer blend of PLLA, PCL and PHBV. It is taught that blending PCL and PHBV with PLLA offers an effective approach to the development of new polyester-based biomaterials with combinations of mechanical properties which cannot be provided by any of the materials individually.

[0006] It is an aim of certain embodiments of the invention to provide a biodegradable polymer blend. The biodegradable polymer blend may be used to fabricate orthopaedic fixation implants that can be resorbed in vivo.

[0007] The polymer blends of the invention may biodegrade at a quicker rate than prior art polymer blends. The polymer blends of the invention may biodegrade at a quicker rate than prior art polymer blends whilst retaining favourable mechanical properties. The polymer blends of the invention may biodegrade at a quicker rate than prior art polymer blends and have similar, or improved, mechanical properties than prior art polymer blends.BRIEF SUMMARY OF THE DISCLOSURE

[0008] The first aspect of the invention provides a biodegradable polymer blend comprising:poly(L-lactic acid) (PLLA);a polylactide comprising lactate units having the configuration of D-lactic acid and lactate units having the configuration of L-lactic acid (DL-polylactide); andpoly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV).

[0009] Preferably, the DL-polylactide is poly(L-lactide-co-D,L-lactide). It is also preferable that the polymer blend also comprises polycaprolactone (PCL). A preferred embodiment is therefore a biodegradable quaternary polymer blend consisting of:poly(L-lactic acid) (PLLA);poly(L-lactide-co-D,L-lactide) (PLDL);poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV); andpolycaprolactone (PCL).

[0010] The second aspect of the invention provides a polymer composite comprising: the polymer blend of the first aspect of the invention; and an additive. Preferably, the additive is a bioceramic.

[0011] The third aspect of the invention provides an implant (e.g. an orthopaedic fixation implant) comprising the polymer blend of first aspect of the invention or the polymer composite of the second aspect of the invention.

[0012] The fourth aspect of the invention provides a process for forming a polymer blend of the first aspect of the invention, the process comprising blending PLLA, DL-polylactide (e.g. PLDL), PHBV, and, optionally, PCL, to form the polymer blend.

[0013] The fifth aspect of the invention provides a process for forming a polymer composite of the second aspect of the invention, the process comprising blending PLLA, DL-polylactide (e.g. PLDL), PHBV, the additive and, optionally, PCL, to form the polymer composite.

[0014] The sixth aspect of the invention provides a process for forming an implant (e.g. an orthopaedic fixation implant) of the third aspect of the invention, the process comprising forming the implant from the polymer blend of the first aspect or the polymer composite of the second aspect of the invention.

[0015] The seventh aspect of the invention provides a method of bone fracture treatment comprising attaching the implant of the third aspect of the invention, wherein the implant is an orthopaedic fixation implant, to a fractured bone in order to realign, support, and / or prevent movement of the fractured bone.

[0016] The eighth aspect of the invention provides a method of spinal fusion comprising positioning the implant of the third aspect of the invention, wherein the implant is an orthopaedic fixation implant, between two adjacent vertebrae. In this aspect, the orthopaedic fixation implant is typically a spinal cage.

[0017] The inventors have found that the inclusion of DL-polylactide (e.g. PLDL) in a polymer blend comprising PLLA and PHBV (and optionally PCL) increases the biodegradability of the polymer blend while retaining its mechanical properties. This is surprising because increasing biodegradability will usually adversely affect mechanical properties. The polymer blend can therefore be formed into implants (e.g. orthopaedic fixation implants) that have the necessary mechanical properties whilst biodegrading at a preferred rate. When this implant is anorthopaedic fixation implant, this means that the implant can support the healing of a fracture for as long as is needed but will disappear eventually. Furthermore, the blend already contains PHBV (and optionally PCL). Although these are themselves biodegradable, the blend does not biodegrade at a sufficiently quick rate without the DL-polylactide (e.g. PLDL).Polymer Blend

[0018] The biodegradable polymer blend comprises a polylactide comprising lactate units having the configuration of D-lactic acid and lactate units having the configuration of L-lactic acid (herein referred to as DL-polylactide). The DL-polylactide may consist essentially of lactate units. The DL-polylactide may be a copolymer of D-lactide and L-lactide. The DL-polylactide may be a polymer of DL-lactide. The DL-polylactide may be a copolymer of L-lactide and D,L-lactide. The DL-polylactide may be a copolymer of D-lactide and D, L-lactide. The polylactide may be a polymer of meso-lactide. The DL-polylactide may be a copolymer of L-lactide and meso-lactide. The DL-polylactide may be a copolymer of D-lactide and meso-lactide.

[0019] The DL-polylactide may be derived from the ring-opening polymerization of L-lactide and D-lactide. The DL-polylactide may be derived from the ring-opening polymerization of D,L-lactide. The DL-polylactide may be derived from the ring-opening polymerization of D, L-lactide and L-lactide, D-lactide, meso-lactide, or combinations thereof. The DL-polylactide may be derived from the ring-opening polymerization of meso-lactide. The DL-polylactide may be derived from the ring-opening polymerization of meso-lactide and L-lactide, D-lactide, DL-lactide, or combinations thereof. The polylactide may be derived from the ring-opening polymerization of D, L-lactide and L-lactide.

[0020] It may be that the DL-polylactide is poly(D, L-lactide) (PDLLA). Preferably, the polylactide is poly(L-lactide-co-D, L-lactide) (PLDL).

[0021] The polymer blend may comprise up to 50 wt% DL-polylactide (e.g. PLDL). The polymer blend may comprise up to 35 wt% DL-polylactide (e.g. PLDL). The polymer blend may comprise at least 1 wt% DL-polylactide (e.g. PLDL). The polymer blend may comprise at least 2.5 wt% DL-polylactide (e.g. PLDL). The polymer blend may comprise from 5 to 25 wt% DL-polylactide (e.g. PLDL). The polymer blend may comprise from 7.5 to 17.5 wt% DL-polylactide (e.g. PLDL).

[0022] It may be that the inherent viscosity of the DL-polylactide (e.g. PLDL) is in the range from 0.5 to 7.5 dL / g. It may be that the inherent viscosity of the DL-polylactide (e.g. PLDL) is in the range from 1.5 to 6 dL / g, e.g. in the range from 2 to 5.5 dL / g. It may be that the inherent viscosity of the DL-polylactide (e.g. PLDL) is in the range from 2.5 to 5 dL / g, e.g. in the range from3 to 4.5 dL / g. It may be that the inherent viscosity of the DL-polylactide (e.g. PLDL) is in the range from 3.2 to 4.3 dL / g.

[0023] It may be that the molecular weight of the DL-polylactide (e.g. PLDL) is in the range from 100,000 to 1,000,000, e.g. in the range from 500,000 to 1,000,000. It may be that the molecular weight of the DL-polylactide (e.g. PLDL) is in the range from 500,000 to 900,000, e.g. in the range from 600,000 to 900,000.

[0024] The polymer blend may comprise up to 95 wt% PLLA. The polymer blend may comprise up to 90 wt% PLLA. The polymer blend may comprise at least 40 wt% PLLA. The polymer blend may comprise at least 50 wt% PLLA. The polymer blend may comprise from 60 to 85 wt% PLLA. The polymer blend may comprise from 65 to 82.5 wt% PLLA.

[0025] It may be that the inherent viscosity of the PLLA is in the range from 0.5 to 7.5 dL / g. It may be that the inherent viscosity of the PLLA is in the range from 1.5 to 6 dL / g, e.g. is in the range from 2 to 5.5 dL / g. It may be that the inherent viscosity of the PLLA is in the range from 2.5 to 5 dL / g, e.g. 3 to 4.5 dL / g. It may be that the inherent viscosity of the PLLA is in the range from 3.2 to 4.3 dL / g.

[0026] It may be that the molecular weight of the PLLA is in the range from 100,000 to 800,000, e.g. in the range from 250,000 to 750,000. It may be that the molecular weight of the PLLA is in the range from 500,000 to 700,000, e.g. in the range from 600,000 to 700,000. It may be that the molecular weight of the PLLA is in the range from 625,000 to 675,000.

[0027] The polymer blend may comprise up to 20 wt% PHBV. The polymer blend may comprise up to 15 wt% PHBV. The polymer blend may comprise at least 1 wt% PHBV. The polymer blend may comprise at least 2.5 wt% PHBV. The polymer blend may comprise from 2.5 to 10 wt% PHBV.

[0028] The PHBV may have a PHV (polyhydroxyvalerate) content of less than 50 mol%. The PHBV may have a PHV content of less than 20 mol%, e.g. less than 15 mol%. The PHBV may have a PHV content of greater than 2.5 mol%, e.g. greater than 5 mol%. The PHBV may have a PHV content in the range from 6 to 10 mol%. The PHBV may have a PHV content of about 8 mol%.

[0029] In preferred embodiments, the polymer blend further comprises PCL. It may be that the blend comprises up to 12.5 wt% PCL. The blend may comprise up to 10 wt% PCL. The blend may comprise at least 1 wt% PCL. The blend may comprise at least 2.5 wt% PCL. The inventors have found that the inclusion of PCL increases the fracture toughness and elongation at break of the blend. However, despite itself being biodegradable, the inclusion of too muchPCL reduces the rate of degradation of the blend, counteracting the effect of the DL-polylactide (e.g. PLDL).

[0030] It may be that the molecular weight of the PCL is in the range from 10,000 to 250,000, e.g. is in the range from 15,000 to 150,000. It may be that the molecular weight of the PCL is in the range from 50,000 to 100,000.

[0031] In an embodiment, the polymer blend comprises:from 40 to 90 wt% PLLA;from 5 to 30 wt% DL-polylactide (e.g. PLDL);from 1 to 15 wt% PCL; andfrom 1 to 15 wt% PHBV.

[0032] In an embodiment, the polymer blend comprises:from 60 to 90 wt% PLLA;from 5 to 30 wt% DL-polylactide (e.g. PLDL);from 1 to 15 wt% PCL; andfrom 1 to 15 wt% PHBV.

[0033] In an embodiment, the polymer blend comprises:from 65 to 85 wt% PLLA;from 7.5 to 20 wt% DL-polylactide (e.g. PLDL);from 2.5 to 12.5 wt% PCL; andfrom 1 to 10 wt% PHBV.

[0034] Typically, the wt% of DL-polylactide (e.g. PLDL) in the polymer blend is greater than the wt% of PCL. It may be that the wt% of DL-polylactide (e.g. PLDL) in the polymer blend is greater than or equal to 1.1 times, e.g. greater than or equal to 1.25 times, the wt% of PCL in the polymer blend. It may be that the wt% of DL-polylactide (e.g. PLDL) in the polymer blend is greater than or equal to 1.5 times, e.g. greater than or equal to 1.75 times, the wt% of PCL in the polymer blend. It may be that the wt% of DL-polylactide (e.g. PLDL) in the polymer blend is greater than or equal to 2 times the wt% of PCL in the polymer blend.

[0035] The polymer blend may comprise at least one additional biodegradable polymer in addition to PLLA, DL-polylactide (e.g. PLDL), PHBV, and optionally PCL. The at least one biodegradable polymer may be selected from polydioxanone and copolymers thereof, polyglycolide and copolymers thereof, poly(trimethylene carbonate) and copolymers thereof, polyhydroxybutyrate and (other) copolymers thereof, copolymers of polylactic acid, coplolymers of PCL, biopolymers, and mixtures thereof.

[0036] Copolymers of lactic acid include polyethylene glycol diblock and triblock polymers, poly(lactide-co-glycolide) (PLGA), and poly(tri methylene carbonate) copolymers. Copolymers of PCL include glycolide copolymers, lactide copolymers, poly(trimethylene carbonate) copolymers, and polyethylene glycol diblock and triblock polymers.

[0037] Illustrative biopolymers include, but are not limited to, proteins (e.g., collagen, elastin, gelatin, and keratin), and polysaccharides (e.g., cellulose, carboxymethylcellulose, hydroxypropyl cellulose, carboxymethyl starch, dextran, pectin, alginic acid, carrageenan, heparin, gellan gum, agarose, hyaluronic acid, chitin, chitosan, or a pharmaceutically acceptable salt thereof).

[0038] It may be that the biodegradable polymer blend consists of PLLA, DL-polylactide and PHBV. It may be that the biodegradable polymer blend consists of PLLA, DL-polylactide, PHBV and PCL.

[0039] It may be that the polymer blend is surface modified. It may be that the polymer blend is surface functionalised with a biopolymer, e.g. a polynucleotide, polypeptide, or polysaccharide. The polymer blend may be surface functionalised with a protein. The protein may be selected from collagen, fibronectin, laminin, elastin, albumin and gelatin. The protein may be collagen (e.g. type I collagen). The protein may be the inducible soluble recombinant form of the T cell co-stimulator (ICOS-Fc).Polymer Composite

[0040] The second aspect of the invention provides a polymer composite comprising: the polymer blend of the first aspect of the invention; and an additive. The polymer composite may comprise two or more additives. Typically, the additive, or additives, will be dispersed throughput the polymer blend, which acts as a matrix.

[0041] The additive will typically be a biomaterial. The biomaterial may be a bioceramic. Bioceramics include alumina, zirconia, bioactive glass, glass ceramics, hydroxyapatite, calcium silicate, resorbable calcium phosphate, and mixtures thereof. The bioceramic may comprise hydroxyapatite. The hydroxyapatite may be nanohydroxyapatite. The bioceramic may comprise a bioactive glass, e.g. mesoporous bioactive glass.

[0042] The bioceramic may comprise a strontium-substituted bioceramic. The bioceramic may comprise strontium-substituted hydroxyapatite, e.g. strontium-substituted nanohydroxyapatite. The bioceramic may comprise a strontium-substituted bioactive glass, e.g. strontium-substituted mesoporous bioactive glass.

[0043] The polymer composite may comprise nanohydroxyapatite and mesoporous bioactive glass.

[0044] The polymer blend of the present invention may be used for drug delivery. The additive may therefore comprise a drug. Means of encapsulating the drug additive within the polymer blend are known in the art. For example, it may be that the polymer composite is a polymer microsphere wherein the drug additive is dispersed throughout the polymer microsphere matrix. It may be that the polymer composite is a polymer fiber (e.g. a polymer nanofiber) comprising the drug additive.

[0045] It may be that the polymer composite comprises up to 15 wt% of the additive. It may be that the polymer composite comprises up to 10 wt% of the additive. It may be that the polymer composite comprises up to 7.5 wt% of the additive. It may be that the polymer composite comprises up to 10 wt% of the additive. The polymer composite may comprise at least 0.5 wt% of the additive. It may be that the polymer composite comprises from 1 to 6 wt% of the additive. It may be that the polymer composite comprises from 1 to 6 wt% of nanohydroxyapatite.Implant

[0046] The implant may be an orthopaedic fixation implant. It may be that the orthopaedic implant is an implant selected from a fracture fixation plate, a spinal cage, a screw, a nail or rod, and a wire or pin. It may be that the orthopaedic implant is a fracture fixation plate. It may be that the orthopaedic implant is a spinal cage.

[0047] It may be that the orthopaedic implant is fracture fixation plate for a fractured bone, wherein the bone is selected from the femur (thighbone), the radius (forearm), the ulna (forearm), a metacarpal bone (in the hands), the tibia and the fibula.

[0048] The fracture fixation plate may be a compression plate, an arthrodesis plates, or an osteotomy plate.

[0049] The implant may be a drug carrier / implantable drug delivery system, wherein the implant comprises the polymer composite of the second aspect of the invention and the additive comprises a drug. The drug may be dispersed throughout the polymer blend matrix. In these embodiments the drug may be free to diffuse out of the polymer matrix in vivo. It may be that the drug is encapsulated in a polymer or ceramic additive, which is dispersed throughout the polymer blend matrix. In these embodiments the encapsulated drug may be released when the polymer composite biodegrades in vivo. Alternatively, the drug may be attached to the surface of the polymer composite.

[0050] When the implant is an orthopaedic implant, it may be that the drug is an osteoporosis drug. The osteoporosis drug may be a bisphosphonate, e.g. alendronate, risedronate, ibandronate, or zoledronic acid.Polymer Blend Formation

[0051] It may be that the PLLA, DL-polylactide (e.g. PLDL), PHBV and, optionally, PCL are extruded to form the polymer blend. For example, the blending may be carried out using a twin-screw extruder.

[0052] The process may comprise adding pellets of PLLA, DL-polylactide (e.g. PLDL), PHBV and, optionally, PCL, to an extruder hopper before blending the pellets in a twin-screw extruder. It may be that two extrusions are carried out. The temperature at which the second extrusion is carried out may be lower than the temperature at which the first extrusion is carried out.

[0053] It may be that the polymer blend is produced as a filament.Polymer Composite Formation

[0054] It may be that the PLLA, DL-polylactide (e.g. PLDL), PHBV, additive, and, optionally, PCL are extruded to form the polymer composite. For example, the blending may be carried out using a twin-screw extruder.

[0055] The process may comprise adding pellets of PLLA, DL-polylactide (e.g. PLDL), PHBV and, optionally, PCL, and the additive to an extruder hopper before blending in a twin-screw extruder. It may be that two extrusions are carried out. The temperature at which the second extrusion is carried out may be lower than the temperature at which the first extrusion is carried out.

[0056] It may be that the polymer pellets (e.g. PLLA pellets) are first incubated in a paste comprising the additive (e.g. nanohydroxyapatite and / or mesoporous bioactive glass). The pellets may be incubated at for at least 12 hours (e.g. around 24 hours) at room temperature. After incubation the pellets may be dried, e.g. for 12 hours at 50 °C.

[0057] It may be that the polymer composite is produced as a filament.Orthopaedic Fixation Implant Fabrication

[0058] The process for forming an implant (e.g. an orthopaedic fixation implant) of the third aspect of the invention may comprise 3D printing the implant from the polymer blend of the first aspect of the invention or from the polymer composite of the second aspect of the invention. The 3D printing may be fused deposition modelling.

[0059] The process for forming an implant (e.g. an orthopaedic fixation implant) of the third aspect of the invention may comprise moulding the implant from the polymer blend of the first aspect of the invention or from the polymer composite of the second aspect of the invention. The moulding may be a moulding selected from rotational moulding, injection moulding, blow moulding, compression moulding, and extrusion moulding.

[0060] When forming an implantable drug delivery system (IDDS), the drug additive may be incorporated within the implant at various stages of the manufacturing procedure. For example, it may be that the PLLA, DL-polylactide (e.g. PLDL), PHBV, drug additive, and, optionally, PCL are extruded (e.g. twin-screw extruded) to form a polymer composite. The IDDS may then be fabricated from the polymer composite, e.g. via the moulding or 3D printing methods mentioned above. Alternatively, the polymer blend of the first aspect of the invention may be formed before the IDDS is fabricated from the polymer blend and the drug additive, e.g. via the moulding methods mentioned above.

[0061] The implant (e.g. orthopaedic fixation implant) may be surface modified. The implant (e.g. orthopaedic fixation implant) may be surface functionalised with a biopolymer, e.g. a polynucleotide, polypeptide, or polysaccharide. The implant may be surface functionalised with a protein. The protein may be selected from collagen, fibronectin, laminin, elastin, albumin and gelatin. The protein may be collagen (e.g. type I collagen). The protein may be the inducible soluble recombinant form of the T cell co-stimulator (ICOS-Fc).Bone Fracture Treatment

[0062] In the method of the seventh and eighth aspects of the invention, the orthopaedic fixation implant is typically not removed once attached to the fractured bone or positioned between vertebrae. The orthopaedic fixation implant is intended to be resorbed in vivo.

[0063] In the seventh aspect of the invention the fractured bone may be selected from the femur (thighbone), the radius (forearm), the ulna (forearm), a metacarpal bone (in the hands), the tibia and the fibula. The fracture may be a periprosthetic fracture.BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:Figure 1 shows the percentage mass loss for each of the assessed four-polymer blends.Figure 2 shows the GPC of the assessed four-polymer blends.Figure 3 shows the ATR-FTIR spectrum for the four-polymer blend 70 / 15 / 10 / 5 before and after 2 months of accelerated degradation.Figure 4 shows the mechanical characteristics of the blend (PLLA / PCL / PHBV (90.5.5)) material with different weight percentage incorporation of hydroxyapatite.Figure 5 is a PLLA filament (raw) and with different ratios of incorporated nano-HA. Figure 6 is an SEM image showings micro sized agglomerations of HA across the cross section of the PLLA plus 10% HA filament.Figure 7 shows the EDS elemental analysis of an Sr-nano-HA enriched PLLA / PCL / PHBV (90 / 5 / 5) blend.Figure 8 is an SEM image of a cross section of a PLLA / PCL / PHBV (90 / 5 / 5) blend enriched with nano-HA and MBG.Figure 9 is a further SEM image of a cross section of a PLLA / PCL / PHBV (90 / 5 / 5) blend enriched with nano-HA and MBG.Figure 10 shows the UV-VIS spectroscopy for the toluidine blue staining used to quantify the carboxyl groups on a PLLA / PCL / PHBV (90 / 5 / 5) blend surface following hydrolysis under various conditions.Figure 11 shows the UV-VIS spectroscopy for the toluidine blue staining used to quantify the carboxyl groups on a PLLA / PCL / PHBV (90 / 5 / 5) blend surface following hydrolysis with varying concentrations of NaOH / methanol.Figure 12 shows the UV-VIS spectroscopy for the Sirius red staining used to assess the degree of collagen fixation on a PLLA / PCL / PHBV (90 / 5 / 5) blend surface.Figure 13 shows the UV-VIS spectroscopy for the acid orange II staining used to quantity the amine groups on the surface of a PLLA / PCL / PHBV (90 / 5 / 5) blend.Figure 14 shows SEM images of filament sections to assess surface damage with aminolysis condition used for ICOS-Fc fixation onto the surface of a PLLA / PCL / PHBV (90 / 5 / 5) blend.Figure 15 is a fluorescence image of a PLLA / PCL / PHBV (90 / 5 / 5) filament fluoresced with ICOS-Fc (and a control filament) using a fluorescence microscope (Leica).Figure 16 is a pictorial representation of the animal model used in the in vivo assessment. The highlighted box on the centre medial bone indicates the periosteal stripping.The dots indicate the created circular bicortical bony defects, each with a diameter of 0=6mm and positioned at approximately 30mm apart.Figure 17 is a pictorial representation of an implants 1 and 2 and the tibial defects assessed in the in vivo assessment, with M standing for medial and L standing lateral.Figure 18 are the medial-lateral X-rays after 9 weeks comparing implants 1 (A) and 2 (B) in the in vivo assessment.Figure 19 shows the cross-sectional views of the sample 002 (implant 1) and of the sample 007 (implant 2) groups in three different planes. On the left the samples where the periosteum was removed and on the right those where the periosteum was left in place.Figure 20 depicts the three-dimensional representations of the sample 002 (implant 1 ) and 007 (implant 2).Figure 21 illustrates the histological images of samples with (P) and without periosteum (NP) from one implant 1 (001) and one implant 2 (008) animal, captured after embedding in resin. In the first column, there is an overview of the cortical bone region involved in the surgical procedure. The second column provides an enlarged view of the area corresponding to the surgically created bone defect (2.5x magnification, stained with Toluidine Blue / Fast Green). The third column displays a representative fluorescence image showing the detectable labelling from the administered fluorochromes (20x magnification), including oxytetracycline, alizarin red, and calcein blue.Figure 22 illustrates the histological images displaying bone formation and the deposition of extracellular matrix with intermingled cellular elements and osteoblasts along the bone trabeculae. The presence of osteocytes within the osteocyte lacunae is indicated by red arrows. These images are magnified at 40x and represent an implant 2 sample (a) and an implant 1 sample (b), both subjected to Toluidine Blue / Fast Green staining.Figure 23 illustrates the histological image featuring a panoramic view of the defect site, highlighting the accumulation of recently generated bone connecting from both sides to form a bone bridge. In the image legend, '*' represents newly formed bone, and '§' denotes preexisting bone. The image was captured at a magnification of 2.5x and stained using Toluidine Blue / Fast Green (008_P sample, test group with periosteum).Figure 24 illustrates the accumulation of connective tissue in the upper boundary of the cortical defect. The image was taken at an 8x magnification (003_NP sample) and stained with Toluidine Blue / Fast Green.Figure 25 illustrates the representative histological images of peri-implant bone, specifically capturing the bone deposition front at the cortical defect level. The upper arrow highlights the pre-existing bone front, while the lower arrow indicates the newly deposited bone front. Panel A shows the image at 2.5x magnification, and Panel B provides a closer view at 40x magnification (005_P sample), with Toluidine Blue / Fast Green staining.Figure 26 shows the plots of the average and standard deviation recorded for each measured mechanical property of implant 1 and 2. The difference between groups was not statistically significant.DETAILED DESCRIPTIONDefinitions

[0065] A polymer blend is a mixture (typically a homogeneous mixture) of two or more different polymer types.

[0066] Poly(L-lactide-co-D, L-lactide) (PLDL) is a copolymer of L-lactide and D-lactide. PLDL is typically formed through the ring-opening polymerization of L-lactide and D, L-lactide. It may be that the molar ratio of L-lactide:D, L-lactide is in the range from 50:50 to 90:10. It may be that the ratio of L-lactide:D, L-lactide is in the range from 60:40 to 80:20. It may be that the ratio of L-lactide:D, L-lactide is about 70:30.

[0067] D,L-lactide is a racemic mixture of D-lactide and L-lactide.

[0068] meso-lactide has the following structure:

[0069] The polymer blend of the present invention may be surface modified / functionalised in order to introduce different chemical functional groups to the surface of the polymer blend. The surface of a polymer blend may be modified via methods known in the art. The polyester constituents (PLLA, DL-polylactide (e.g. PLDL), PHBV, and, optionally, PCL) of the polymer blend may be hydrolysed to form hydroxyl and carboxylic acid groups through an alkaline treatment (e.g. using NaOH / EtOH). Amino groups can be introduced through aminolysis reactions using diamine compounds. Plasma treatment using various feed gases, such as oxygen, argon, nitrogen and carbon dioxide, can also be applied to introduce carboxylic acid, amine, and hydroxyl groups to the surface of the polymer blend.

[0070] In some embodiments the polymer blend is surface functionalised with a protein. The polymer blend may be surface functionalised with a protein by carrying out an initial hydrolysis(e.g. as per Example 4.1 ) or aminolysis (e.g. as per Example 4.3) to yield surface -COOH and -NH2groups, respectively, followed by crosslinking with the protein (e.g. per Example 4.2 or Example 4.4, using EDC / NHS).

[0071] It is intended that the wt%s of PLLA, DL-polylactide (e.g. PLDL), PCL and PHBV in the polymer blend of the present invention specified herein do not include the wt% of any functional groups (in embodiments where the polymer blend is surface modified / functionalised).

[0072] Inherent viscosity (IV) is a viscometric method for measuring molecular size. IV is based on the flow time of a polymer solution through a narrow capillary relative to the flow time of the pure solvent through the capillary. The units of IV are typically reported in decilitres per gram (dL / g). It may be that the inherent viscosity is determined according to ISO 1628-1 :2024.

[0073] Polymer viscosity may also be inferred from melt flow measurements performed in accordance with ISO 1133-1 :2022 under specified temperature and load conditions. For PLLA and DL-polylactide (e.g. PLDL), the melt flow index may be determined in accordance with ISO 1133 under standard temperature and load conditions conventionally applied for polylactide materials, e.g. at temperatures in the range of about 190 °C to about 210 °C under a load of about 2.16 kg.

[0074] The molecular weight, orweight average molecularweight (Mw), of a polymer is defined by the following formula:where M, is the molecularweight of a particular chain and Ni is the number of chains of that molecularweight. The Mw may be measured using gel permeation chromatography (GPC) relative to a set of standard polymers with a specified eluent solvent system.

[0075] The term “additive” is intended to cover any non-polymeric biocompatible molecule.

[0076] A “biomaterial” is any material exploited in contactwith living tissues, organisms, or microorganisms. Biomaterials typically interact with biological systems for a medical purpose. The medical purpose may be therapeutic (e.g., to treat, augment, repair, or replace a tissue function of the body) or a diagnostic one.

[0077] A “bioceramic” is any ceramic, glass, or glass-ceramic that is used as a biomaterial. Bioceramics include metal oxide bioceramics.

[0078] An implant (or medical implant) is a device that is to be placed inside or on the surface of the human or animal body. Implants are typically intended for use in the diagnosis,prevention, treatment, or cure of diseases or other conditions. Implants may be manufactured to replace a missing biological structure, support a damaged biological structure, or enhance an existing biological structure. An implant may be an implantable drug delivery system (IDDS). Implants may be used for birth control, or for cosmetic purposes. The polymer blend of the present invention is particularly suited to form implants that are not intended to remain permanently implanted due to their ability to biodegrade in vivo.

[0079] Compression plates are plates used for fractured bones. Arthrodesis plate are plates are used to stabilize or immobilize a damaged joint. Osteotomy plates are used for bone lengthening and to correct certain orthopaedic deformities.

[0080] Fracture fixation plates are internal splints that hold the broken bones together. They are typically attached with screws and may be left in place or removed once healing is complete.

[0081] Orthopaedic screws can be used alone to hold a fracture, as well as with plates, rods, or nails. They may be left in place or removed once healing is complete.

[0082] Orthopaedic nails or rods are typically used in the fracture of long bones. The rod or nail can be inserted through the hollow centre of the bone (usually containing some bone marrow). They may be left in place after healing is complete.

[0083] Orthopaedic wires and pins are often used to pin the bones back together, used to hold pieces of bone together that a too small to be fixed by screws. Wires are usually removed after a certain amount of time but may be left in permanently.

[0084] A “drug” is any substance or combination of substances that is intended to treat, prevent or diagnose a disease, or to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action. Illustrative drugs include analgesics (e.g., non-opioid analgesics and opioid analgesics, anesthetics (e.g., local anesthetics); antibacterials (e.g., aminoglycosides, cephalosporins, penicillins, and other betalactams, macrolides, quinolones, sulfonamides, tetracyclines, antifolates, glycopeptides, lincomycins, nitrofurans, and oxazolidinones); anticonvulsants (e.g., calcium channel modifying agents, gamma-aminobutyric acid (gaba) augmenting agents, glutamate reducing agents, and sodium channel inhibitors); antidementia agents (e.g., cholinesterase inhibitors, glutamate pathway modifiers, antidementia agents); antidepressants (e.g., monoamine oxidase inhibitors, serotonin / norepinephrine reuptake inhibitors, and tricyclics); antidotes, deterrents, and toxicologic agents; antiemetics; antifungals; antigout agents; anti-inflammatory agents (e.g., glucocorticoids and nonsteroidal anti-inflammatory drugs); antimigraine agents (e.g., abortiveand prophylactic antimigraine agents); antimyasthenic agents (e.g., parasympathomimetics); antimycobacterials (e.g., antituberculars); antineoplastics (e.g., alkylating agents, antiangiogenic agents, antiestrogens / modifiers, antimetabolites, aromatase inhibitors, 3rd generation, molecular target inhibitors, monoclonal antibodies, and retinoids); antiparasitics (e.g., anthelmintics, antiprotozoals, and pediculicides / scabicides); antiparkinson agents; antipsychotics (e.g., atypical and conventional antipsychotics); antispasticity agents; antivirals (e.g., anti-cytomegalovirus agents, antihepatitis agents, antiherpetic agents, anti-human immunodeficiency virus agents, fusion inhibitors, anti-hiv agents, and anti-influenza agents); anxiolytics (e.g., antidepressants); bipolar agents; blood glucose regulators (e.g., antidiabetic agents, glycemic agents, and insulins); blood products / modifiers / volume expanders (e.g., anticoagulants, blood formation products, coagulants, and platelet aggregation inhibitors); cardiovascular agents (e.g., alpha-adrenergic agonists, alpha-adrenergic blocking agents, antiarrhythmics, beta-adrenergic blocking agents, calcium channel blocking agents, diuretics, dyslipidemics, renin-angiotensin-aldosterone system inhibitors, and vasodilators); central nervous system agents (e.g., amphetamines, and non-amphetamines); dental and oral agents; dermatologicalagents; enzyme replacements / modifiers; gastrointestinal agents (e.g., antispasmodics, histamine2blocking agents, irritable bowel syndrome agents, protectants, and proton pump inhibitors); genitourinary agents (e.g., antispasmodics, benign prostatic hypertrophy agents, phosphate binders); hormonal agents; immunological agents (e.g. immune stimulants, such as vaccines, immune suppressants, immunizing agents, passive, and immunomodulators); inflammatory bowel disease agents (e.g., glucocorticoids, salicylates, and sulfonamides); metabolic bone disease agents; ophthalmic agents (e.g., ophthalmic anti-allergy agents, ophthalmic antiglaucoma agents, ophthalmic anti-inflammatories, ophthalmic prostaglandin, and prostamide analogs); otic agents; respiratory tract agents (e.g., antihistamines, anti-inflammatories, inhaled corticosteroids, antileukotrienes, bronchodilators, mast cell stabilizers, and pulmonary antihypertensives); sedatives, skeletal muscle relaxants; and therapeutic nutrients, minerals, and electrolytes.

[0085] A polymer microsphere is a micron-sized (1-100 pm diameter) spherical vehicle comprising a continuous polymeric phase (matrix). A drug additive may be dispersed or dissolved within the matrix. Polymer microspheres may be made according to methods known in the art, e.g. emulsion polymerization or solvent evaporation.

[0086] Polymer nanofibers may be made according to methods known in the art, e.g.electrospinning.

[0087] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0088] Throughout the specification these abbreviations have the following definition:ANOVA analysis of varianceATR attenuated total reflectanceBFR rate of bone formation per bone areaBV / TV bone volume percentageDSC differential scanning calorimetryEDC / NHS 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / N-hydroxysuccinimide EDS energy dispersive x-ray spectroscopyFTIR Fourier-transform infrared spectroscopyGPa gigapascalsGPC gel permeation chromatographyHA hydroxyapatiteICOS-Fc inducible soluble recombinant form of the T cell co-stimulatorkN kilonewtonMAR mineral apposition rate per dayMBG mesoporous bioactive glassMES 2-(N-morpholino)ethanesulfonic acidmicro-CT micro-computed tomographyMPa megapascalMS / BS percentage of mineralizing surface per bone surfaceNP absence of periosteum0 diameterP presence of periosteumPBS phosphate buffer solutionPCL polycaprolactonePHBV poly(3-hydroxybutyrate-co-3 hydroxyvalerate)PLDL poly(L-lactide-co-D,L-lactide)PLLA poly(L-lactic acid)S.D (SD) standard deviationSEM scanning electron microscopyTb.N number of trabeculaeTb.Sp trabecular spacingTb.Th trabecular thicknessUV-VIS ultraviolet-visible spectroscopyVOI volume of interest

[0089] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention areto be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0090] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.EXAMPLESMaterials and MethodsPolymer Materials

[0091] The polymers used in the following examples are detailed in Table 1 :Table 1Filament Production

[0092] For production of materials for 3D printing, twin screw extrusion was used to produce filaments. Polymer pellets were placed in an extruder hopper and with careful optimization of extrusion temperatures across 5 zones of the extruder and speed of the screws and haul off unit, filament (diameter ~1.75 mm) was achieved. For each of the blend materials (2 polymers or more) and for enriched materials, two extrusions were carried out. The second extrusion was always carried out at a lower temperature to the first one for all blend materials to ensurehomogenous blending of the polymers and additives whilst limiting thermal degradation of the polymers.Mechanical Testing

[0093] AShimadzu universal tester with a 1 kN load cell was used for tensile testing of filament. Testing was based on a displacement setup with a speed of 30 mm / min. Termination of the test occurred when either material rupture or when 300 mm of material displacement was reached. Tests were repeated for n = 3 and averaged. All testing was conducted at room temperature (22 °C).Chemical and Optical Characterization

[0094] Fourier transform infrared spectroscopy (Perkin Elmer), gel permeation chromatography (GPC) and differential scanning calorimetry (DSC) were used to investigate the chemical characteristics of the developed materials. For FTIR, spectra were recorded from 500 - 4000 cm'1and 16 scans averaged. DSC used a heating rate of 10 °C / min to assess the melt profile of each material blend. GPC (Agilent Technologies) was run on polymer liquid samples after they had been dissolved down in chloroform. Scanning electron microscopy (SEM) (Hitachi) was used to microscopically assess filaments and energy dispersive x-ray spectroscopy (EDS) (Bruker) was used to analytically inspect the elemental composition of the materials under SEM.Degradation Characterization

[0095] Filament sections of sole or blend polymer were investigated for degradation characteristics. Materials undergoing these investigations were rinsed in distilled water prior to incubation in phosphate buffer solution (PBS) in glass vials at 50 °C for prolonged periods. These accelerated degradation conditions are consistent for investigatory purposes, to assess degradation on a shorter time scale. The PBS was changed on a weekly basis and pH measured to assess for acidic degradation by-products.Example 1: Four Polymer Blend

[0096] In order to enhance the lengthy degradation seen with the three-polymer blend, PLDL was added and a range of new four polymer blends assessed as highlighted in Table 2.Table 2: comparative 3-polymer blend, 4-polymer blends and the corresponding mechanical data &<

[0097] The maximum incorporation of PLDL was kept at 15% or below to ensure degradation of the material was not too rapid. The mechanical characteristics of the materials show that with the addition of PLDL, there is no compromise to the mechanical properties of the material in comparison to the optimized three polymer blend. This was seen with a consistent maintenance of yield strength and elastic modulus across the blends investigated. All materials also exhibited very similar strain at break despite the varia tion in PCL, albeit in a small amount.Four Polymer Blend Degradation Tests

[0098] Six four-blend filaments underwent accelerated degradation testingfor 8 weeks to assess the effect of incorporation of PLDL to the blends. The material with the greatest percentage mass loss at the end of the 2 months was PLLA / PLDL / PCL / PHBV (70 / 15 / 10 / 5) (Figure 1). This result aligned with those obtained with GPC analysis and molecular weight drop (Figure 2). This signifies that degradation is actively progressing within the material core. The surface of the polymers assessed with ATR-FTIR demonstrate no drastic shift in spectrum changes after the 8 weeks of degradation showing that surface erosion has not yet occurred which is typical of degradation in the later stages in aliphatic polyesters (Figure 3). The incorporation of PLDL into the blend enhanced the rate of degradation (greater mass loss and molecular weight drop) whereas a higher amount of PCL in these blends saw a slower degradation.

[0099] Of the four polymer blends, the PLLA / PLDL / PCL / PHBV (70 / 15 / 10 / 5) was chosen as the optimal blend due to its enhanced degradation whilst maintaining good mechanical properties.Example 3: Polymer Blend Enrichment with nano-HA and / or MBG

[0100] The most promising blends from initial investigatory tests were selected to combine with different amounts of nano-HA (pure and strontium (Sr) substituted) and Sr-containing MBG supplied by Fluidnova (FLU) and POLITO using PLLA / PCL / PHBV (90 / 5 / 5) and PLLA / PLDL / PCL / PHBV (70 / 10 / 15 / 5). Initial investigations were carried out with PLLA alone priorto investigation with the blends. Incorporation of large weight percentages of MBG was found to be difficult, because of the low density of the powder. The nano-HA (pure and Sr substituted) was supplied as a paste formulation by FLU. After preliminary investigations it was found that isolating PLLA pellets in this paste for 24 hours, prior to drying at 50 °C for 12 hours enabled good coating of the polymer pellets. These coated pellets were then extruded as normal as singular or in blend materials with addition of the remaining polymers. It is noted that consideration was taken to use a higher volume of paste when making up samples as the weight percentage of nano-HA was 15%.

[0101] The 90 / 5 / 5 blend had three different weight percentages of nano-HA incorporated: 1%, 2.5% and 5%. The results show that with increasing incorporation of nano-HA into the blend, there is a decline in mechanical properties. 2.5% incorporation allows for a good amount of nano-HA into the material whilst not detrimentally impacting the material mechanical properties (Figure 4, Table 3). The decline in elastic modulus and yield strength of the blend material with 5% nano-HA incorporation is evident.Table 3: Mechanical properties for the enriched blend materials

[0102] Confirmation of nano-HA incorporation into the materials was seen visually and through scanning electron microscopy (SEM) imaging and with energy dispersive spectroscopy (EDS) analysis. By eye, when HA was incorporated with PLLA, a colour change was seen between raw PLLA and materials with different ratios of HA (Figure 5). SEM imaging shows micro sized agglomerations of HA across the cross section of the filament (Figure 6). With EDS analysis, the elemental composition confirms SrHA incorporation (Strontium (Sr), Calcium (Ca) and Phosphorous (P)) (Figure 7).

[0103] A strategy was developed to incorporate MBG powder together with the HA paste. This involved firstly adding MBG powder to the paste and mixing to form a homogenous consistency. The optimized volume of HA paste with MBG powder was found to be 6% wt. and 4% wt. respectively. This combined paste was added to PLLA pellets, incubated for 24 hours at room temperature, and then dried for a further 12 hours at 50oC. The enriched PLLA pellets were then combined with the remaining polymers, dependent upon the blend, prior to extrusion.

[0104] Table 4 displays the mechanical data for the 90 / 5 / 5 blend enriched with 6% wt. nano-HA and 4% wt. MBG. Mechanically, there is a slight deviation in mechanical characteristics; however, this is not significant. MBG and nano-HA incorporation was again confirmed with SEM imaging (Figure 8 and Figure 9). Agglomeration into micro sized particles can be seen, with the micro sized particles evenly distributed across the filament.Table 4: Mechanical data for the enriched blends (90.5.5 (PLLA / PCL / PHBV)) (n = 3)Example 4: Surface Functionalisation

[0105] Preliminary assessments were carried out to graft ICOS-Fc onto the composite polymer (blend 90 / 5 / 5). The ability of collagen to be grafted onto the surface of the polymer was also investigated.

[0106] A range of surface modification methods can be used to alter a materials surface property or to add functional groups to graft biomolecules. Chemical modifications can introduce functional groups onto the surface of a polymer for ensuing modification with biomolecules. Carboxyl and amine groups are two of the most common functional groups which can be exploited in surface functionalization and require activation in aliphatic polyesters. Two ways in which to do so are hydrolysis and aminolysis which introduce carboxylic acid (-COOH) and amine (NH / NH2) groups, respectively. These methods were exploited for use with the composite polymer blend after which ICOS-Fc and collagen were fixated onto the material surface. Preliminary studies found that hydrolysis was most suitable for use to fix collagen. Aminolysis was best used for ICOS-Fc fixation.Example 4.1: Hydrolysis for Collagen Fixation

[0107] Sodium hydroxide (NaOH) in methanol and sodium hydroxide in water were used as solvents to carry out hydrolysis on the polymer surfaces. A series of tests were conducted to find the best concentration to use to expose an appropriate volume of carboxylic acid groups on the polymer blend (PLLA / PCL / PHBV (90 / 5 / 5)) surface. Sections of extruded polymer filament (1 cm) were used with different hydrolysis solutions (2ml) for each condition and repeated (n=3). The hydrolysis solutions initially assessed were 5M NaOH dissolved in methanol, 0.1 M NaOH inwater, 0.5M NaOH in water and 1 M NaOH in water. For the NaOH in methanol solution, time points of 5-, 10-, 15- and 20-mins incubation at room temperature were assessed. For each concentration of NaOH in water (0.1 M, 0.5M and 1 M), a time point of 60 minutes was assessed. The polymer sections were removed from the hydrolysis solution after their respective incubation periods and thoroughly rinsed in deionized (DI) water. Quantification of carboxyl groups on the material surface were found through Toluidine blue staining quantification using UV-VIS spectroscopy (wavelength (A) = 650 nm). SEM was also conducted to assess surface damage of the solvents on the material filaments. It can be seen that NaOH in methanol elicits a greater proportion of carboxylic groups on the material surface in comparison to NaOH in water. Additionally, the shorter time of incubation of the material with solvent (5 minutes) shows the same density of these -COOH groups on the material surface in comparison to longer times (20 minutes) (Table 5, Figure 10). Given this, NaOH / methanol was deemed the most appropriate solvent to use. Different concentrations of NaOH methanol were then investigated. Table 5: Absorbance data for each of hydrolysis condition on the polymer filament sections (n = 3)

[0108] Figure 11 and Table 6 illustrates results from 1cm sections of blend filament incubated in each solvent concentration for 10 minutes. The lower concentration yields more -COOH groups on the surface of the filament in comparison to the higher concentration. This may be due to polymer degradation at higher concentrations which could be degrading the surface of the filament. Lower concentrations were further investigated, and it was determined that concentrations below 1 M NaOH / methanol were acceptable to use for hydrolysis. This would also ensure there was limited damage to the material surface in comparison to the higher concentrations.Table 6: Absorbance data for each of hydrolysis condition on the polymer filament sections (n = 3)Example 4.2: Fixation of Collagen

[0109] 0.25M and 0.5M NaOH in methanol were assessed on 1 cm long samples of polymer filament in volumes of 2ml for each polymer blend (90 / 5 / 5) section. Three samples of each material were incubated in solution for 5 minutes at room temperature on a shaker. The filaments were then thoroughly washed in DI water prior to incubation with EDC / NHS.

[0110] EDC / NHS was always considered in a 1 :1 ratio and 2-(N-morpholino)ethanesulfonic acid (MES) used as the buffer. EDC / NHS was initially used at pH = 6 during activation of the carboxylate groups. This pH was risen when combining these activated groups to the desired amine attachment molecule, present on the surface of collagen. Two EDC / NHS solution concentrations were investigated, 10 and 100mM, in MES buffer at pH = 6. The polymer filament sections were then incubated with each of these solutions to activate the -COCH terminals for 5 hours at room temperature. After this, the filaments were extracted and isolated with collagen solution (2mg / ml) at a pH of 7.4, overnight in refrigerated conditions (4 °C). Sirius red staining, which stains for collagen, was conducted on the material samples to assess the degree of collagen fixation to the material surface. Table 7 and Figure 12 illustrates the UV-VIS absorbance results for different concentrations of NaOH in methanol with different concentrations of EDC / NHS. It was determined that 0.25M of NaOH in methanol using 10mM of EDC / NHS as the crosslinking solution was the most appropriate to use due to all four samples having a similar output.Table 7: UV-VIS absorbance data for collagen fixation with Sirius red staining (n = 3)Example 4.3: Aminolysis for ICOS-Fc Fixation

[0111] Aminolysis was the chemical method deemed to be appropriate for investigation of fixation of ICOS-Fc onto the polymer surface. Due to the configuration of the ICOS-Fc molecule depicted below:N-terminus C-terminusand its activity being at the N-terminus, the C-terminus must be used for fixation to the polymer surface. For this to occur, the C terminus would require activation with EDC / NHS chemistry and paired with amine groups on the polymer surface.

[0112] 1,6 hexanediamine / isopropanol solution was used with the polymer blend (90 / 5 / 5). Four different concentrations of 1 ,6-hexanediamine in isopropanol were investigated to assess the best concentration to use for optimal -NH2groups: 10, 15, 20 and 25%. Polymer filament sections of 1cm were placed in 2 ml of each concentration of 1 ,6 hexanediamine / isopropanol solution and for n = 3. Each material was incubated at 50 °C for different time periods, prior to being thoroughly rinsed with water.

[0113] The polymer sections were processed for acid orange staining, which was used to quantity of amine (-NH2) groups on the surface. At 37 °C there was no staining of the sections with acid orange when the samples had been kept at room temperature for durations of 40, 50 and 60 mins at the 4 different concentrations. When the temperature was increased to 50 °C, successful results were seen (Table 8, Figure 13).Table 8: UV-VIS spectroscopy for acid orange II staining on the polymer filaments (n = 3)

[0114] Figure 14 illustrates the surfaces of the filaments which have been exposed to different aminolysis conditions. 20% 1 ,6-diamino-hexane / propan-2-ol was used as an optimalconcentration for 40 minutes, given that the surface erosion was not excessive, and a high concentration of amine groups were exposed.Example 4.4: Fixation of ICOS-Fc

[0115] ICOS-Fc was supplied in aliquots of 2 mg, at a concentration of 1.5 mg / ml. The molecule was firstly fluoresced using a Pierce FITC antibody labelling kit (Thermo Fischer Scientific). This would enable visualisation of the antibody attachment to the polymer surface if successful conjugation had occurred. Following the protocol supplied by Thermo Fischer, the best results for fixation of the molecule to the polymer surface were when using 1 mg (0.57 ml ICOS-Fc) of protein, therefore this concentration was used for ICOS-Fc. After fluorescing the ICOS-Fc, the molecule underwent EDC / NHS chemistry (10mM) at pH= 6, in MES buffer to activate the -COOH domain on the ICOS-Fc molecules. 6ml of 10 mM EDC / NHS / MES solution was prepared. This reaction was carried out for 3 hours at room temperature. The same EDC / NHS chemistry process was also carried out with ICOS-Fc not fluoresced as the control. Separately, aminolysis was carried out on 6 polymer blend (90 / 5 / 5) filament sections (1 cm) in 2ml of 20% 1 ,6-diamino-hexane / propan-2-ol for 40 minutes. These sections were then thoroughly washed in DI water. Of the 6 aminolyzed sections, 3 were added to the 2ml of ICOS-Fc / EDC / NHS solution (fluoresced ICOS-Fc) and 3 sections were added to 2ml of ICOS-Fc / EDC / NHS solution (non-fluoresced ICOS-Fc) and incubated at 4 °C overnight. The samples were washed and dried thoroughly in DI water, in dark conditions, prior to subjection to fluorescence imaging the subsequent day. Figure 15 illustrates fluorescence imaging of the fluoresced and non-fluoresced filament sections using a fluorescence microscope (Leica). Successful conjugation of ICOS-Fc to the blend filament sections can be seen due to fluorescence detection of the investigatory filaments and no fluorescence detected for the control section. This confirms that the conditions used to fixate ICOS-Fc to the polymer blend filament are feasible.Summary of Surface Functionalization

[0116] Two methods, using aminolysis and hydrolysis, have successfully shown that collagen and ICOS-Fc can be fixed to the polymer in separate post functionalization processes.Example 6: In Vivo Assessment

[0117] The suitability of orthopaedic fixation implants of the present invention in vivo was assessed. Orthopaedic fixation implants 1 and 2 were 3D printed from a PLLA / PLDL / PCL / PHBV (70 / 15 / 10 / 5) blend. The implants were configured to heal a periprosthetic fracture of the proximal femur and had an anatomically conforming 'c-shaped' configuration to ensure optimalcontact with the curved surface of the femur. The surface of implant 2 was enriched with ICOS-Fc (as per Example 4.4).

[0118] The summary of the pre-clinical assessment is summarised in Table 9.Table 9

[0119] Surgeries to create bone defects and position the implants were conducted by Prof. Antonio Crovace at the Faculty of Veterinary Medicine, University of Bari (UNIBA) on April 26 and 27, 2023. Following aseptic preparation of the right tibia, the surgical procedure involved making a 4 cm medial incision, which provided access to the proximal diaphyseal portion of the tibia (as indicated in Figure 16). In the proximal diaphysis, centered on the medullary cavity, two circular bicortical bony defects were created, each with a diameter of 0=6mm and positioned at approximately 30mm from each other. The periosteum around the first defect was removed to evaluate the implants in supporting bone healing in the presence of damaged periosteum (Figure 17). The implants were securely affixed using two 01.5mm cerclages passed through the scaffold and the tibia before closure of the surgical access.

[0120] All in vivo investigations and administrations were performed as planned and all animals reached the study’s endpoint displaying no signs of discomfort, beside a localized infection identified in one out of twelve animals, which was effectively treated with antibiotics. Figure 18 presents the last of the weekly documentation of defect closure in an implant 2 sheep (007) and an implant 1 sheep (001 ) based on anterior-posterior and medial-lateral X-rays.Qualitatively, the group involving implant 2 appeared to exhibit swifter defect closure. No clinical distinctions were observed between defects with or without periosteum.

[0121] Despite the absence of a notable variance in the daily stride counts between the implant groups in the data analysis during the recovery phase, this study establishes a valuable basis fortracking human patients.

[0122] During the necropsy, the skin wounds were found to be fully healed, while the subcutaneous and peri-implant tissues displayed a noticeable lard-like tissue reaction that covered the periprosthetic implant entirely. The implants themselves remained intact and stable, with some cases showing bone reactions indicative of peri-implant responses. In one sheep, a fistulous pathway was observed, although it did not impact the implantation zone of the scaffold. Radiographic assessments at this stage (refer to Figure 18) did not reveal complete healing of the circular defect, both at the proximal defect (without periosteum) and the distal defect (with periosteum). Examination of the popliteal and inguinal lymph nodes revealed no changes in size, colour, or consistency.

[0123] Figure 19 displays cross-sectional views of samples from both the implant groups in three different planes, while Figure 20 provides their three-dimensional representations. These images offer an overview of the scanned bone segment and allow visualizing the bone growth within the defect.

[0124] Examination of the microtomographic images reveals the presence of the created cortical defect in all samples, with indications of regenerative processes characterized by bone tissue growth from the defect's periphery toward its center. The bone tissue has gradually grown from the periphery toward the center of the defect in test and control samples featuring both periosteum and without periosteum. The outcomes related to bone volume percentage (BV / TV) within the volume of interest (VOI), including trabecular thickness (Tb.Th), spacing (Tb.Sp), and the number of trabeculae (Tb.N), are presented as individual measurements and mean ± SD in Tables 10 and 11.

[0125] Followingthe normality check, a two-way ANOVA was performed to analyse the effect of the presence / absence of ICOS-Fc and that of the presence / absence of periosteum on micro-CT morphometric and dynamic histomorphometric data. The investigation was performed using R software v.4.3.1 (R Core Team) with statistical significance set at p < 0.05.

[0126] Implant 2 outperformed the implant 1 group in absence of periosteum showing a higher percentage of bone volume in the defect and a larger number of thicker trabeculae.Table 10: Morphometric parameters obtained via 3D micro-CT within the respective Volumes of Interest (VOIs) in absence of periosteum (NP)."<

[0127] In presence of periosteum the implant 1 group slightly outperformed the implant 2 group showing a higher percentage of bone volume in the defect and a larger number of thicker trabeculae.Table 11: Morphometric parameters obtained via 3D micro-CT within the respective Volumes of Interest (VOIs) in presence of periosteum (P).

[0128] The statistical analysis revealed that there was no significant interaction between the factors (ICOS-Fc and periosteum) and the micro-CT morphometric results. Further analysis of the simple main effects indicated that the presence or absence of ICOS-Fc in the concentration and form characteristic of the implants tested did not have a statistically significant impact on these results. On the other side, the presence or absence of periosteum did show a statistically significant effect on BV / TV (Fl ,21 = 10.21 , p = 0.004) and Tb.N. (Fl ,21 = 6.15, p = 0.022) results confirming the importance of the contribution of the periosteum in the healing process.

[0129] Figure 21 illustrates the histological images of a selected implant 1 and 2 samples, offering an overview of the cortical bone, a magnified view of the defect area in the diaphysis, and a representative image captured under ultraviolet light to visualize fluorochrome labelling.

[0130] Histologically, at nine weeks the surgical defect area created during the procedure remained distinguishable in all samples. The boundary between the original cortical bone and the newly developed bone tissue is clearly visible. A normal healing process has been detected in test and control samples, with the extracellular matrix deposited concurrently with cellular elements and osteoblasts along the bone trabeculae, and with osteocytes present within the osteocyte lacunae (depicted in Figure 22). In some samples, bone tissue deposition formed a bridge, partially closing the defect with newly formed bone tissue (Figure 23). Conversely, in other cases, the bone deposition fronts originating from both ends of the defect do not meet,resulting in open upper and lower ends (Figure 24). Variations in morphology, structure, and staining intensity using Fast Green dye were evident, with greater intensity displayed (see Figure 25).

[0131] Examination of the fluorescent labels under ultraviolet light has indicated the spread of fluorescence, visible both within and near the defect. While oxytetracycline labelling lacked clarity presumably due to the sheep hormonal status, the labelling with alizarin red and calcein blue fluorochromes was more distinct. It facilitated an assessment of mineralized tissue deposition between the administrations of the two fluorochromes within the defect and at the interface between the pre-existing bone and the new tissue formed in the defect area. The dynamic histomorphometry measurements of MS / BS, MAR, and BFR parameters are presented in Table 12. Implant 2 showed a slightly slower mineral apposition rate per day (MAR) but outperformed implant 1 both with and without periosteum in mineralization of the newly formed tissue (percentage of mineralizing surface per bone surface MS / BS). The rate of bone formation per bone area in cubic micrometres per square micrometer per day (BFR / BS) was similar between groups. Statistical analysis did not highlight any significant interaction between both factors (ICOS-Fc and periosteum) and of their main effects on dynamic histomorphometric results.Table 12: Mean and standard deviation of the calculated dynamic histomorphometric parameters.

[0132] As forthe biomechanicaldata, both implant 1 and 2 groups displayed encouraging indications of defect healing. A comparative analysis of the measured mechanical properties (Mean ± SD) was undertaken through an unpaired t-test to evaluate statistical differences between the implant 1 and 2 groups (Figure 26). This analysis adhered to a 95% confidence level, with statistical significance established for p-values below 0.05. When statistically analysing the biomechanical data with t-test, no notable distinctions in maximum force (Fmax), maximum compressive strength (omax), or the Young's modulus between the groups were found, irrespective of whether periosteum was present or absent.

[0133] In conclusion, both implants 1 and 2 were found to be safe for implantation and exhibited the capability to facilitate the closure of bone defects. A visual examination of the radiographic findings suggested that samples from animals treated with implant 2 appeared to display enhanced healing compared to those treated with implant 1. The biomechanical data exhibited positive but no significant differences in the mechanical properties of the newly formed bone tissue in test and control group.

[0134] The study also shows that the orthopaedic fixation implants of the present invention can be designed to seamlessly integrate with established fixation tools such as plates and bone screws, despite lacking load-bearing functionality, rendering it a versatile therapeutic solution. Surgeons can effectively customize the implants to address a spectrum of fracture patterns and fixation requirements using standard surgical instruments. Noteworthy is their single-use design, coupled with a commendable 6-month shelf-life. Additionally, their compatibility with MRI imaging enhances diagnostic capabilities.REFERENCES1. Jin, W.; Chu, P.K. Orthopedic implants. In Encyclopedia of Biomedical Engineering 1-3;Elsevier: Amsterdam, The Netherlands, 2018; pp. 425-439.2. Moghaddam, N.S.; Andani, M.T.; Amerinatanzi, A.; Haberland, C.; Huff, S.; Miller, M.; Elahinia, M.; Dean, D. Metals for bone implants: Safety, design, and efficacy. Biomanuf. Rev. 2016, 1, 1.3. Hofmann, G. 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Biocompatibility, biodegradation and excretion of polylactic acid (PLA) in medical implants and theranostic systems. Chem. Eng. J. 2018, 340, 9-14.9. Farah, S.; Anderson, D.G.; Langer, R. Physical and mechanical properties of PLA, and their functions in widespread applications — A comprehensive review. Adv. Drug Deliv. Rev. 2016, 107, 367-392.10. Balani, K.; Verma, V.; Agarwal, A.; Narayan, R. Physical, Thermal, and Mechanical Properties of Polymers. In Biosurfaces; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2015; pp. 329-344. 11. Wagner, J.R.; Mount, E.M.; Giles, H.F. Polymer Structure. In Extrusion; Elsevier: Amsterdam, The Netherlands, 2014; pp. 225-232.12. Fortelny, L; Ujcic, A.; Fambri, L.; Slouf, M. Phase Structure, Compatibility, and Toughness of PLA / PCL Blends: A Review. Front. Mater. 2019, 6, 206.13. Ulery, B.D.; Nair, L.S.; Laurencin, C.T. Biomedical applications of biodegradable polymers. J. Polym. Sci. Part B Polym. Phys. 2011, 49, 832-864.14. Gunatillake, P.; Mayadunne, R.; Adhikari, R. Recent developments in biodegradable synthetic polymers. Biotechnol. Annu. Rev. 2006, 12, 301-347.15. Munajad, A.; Subroto, C. FourierTransform Infrared (FTIR) Spectroscopy Analysis of Transformer Paper in Mineral Oil-Paper Composite Insulation under Accelerated Thermal Aging. Energies 2018, 11 , 364.16. Mohammadi, M.S.; Ahmed, I.; Muja, N.; Rudd, C.; Bureau, M.N.; Nazhat, S.N. Effect of phosphate-based glass fibre surface properties on thermally produced poly(lactic acid) matrix composites. J. Mater. Sci. Mater. Med. 2011, 22, 2659-2672.17. Nair, L.S.; Laurencin, C.T. Biodegradable polymers as biomaterials. Prog. Polym. Sci. 2007, 32, 762-798.18. Pouton, C.W.; Akhtar, S. Biosynthetic polyhydroxyalkanoates and their potential in drug delivery. Adv. DrugDeliv. Rev. 1996, 18, 133-162.19. Doyle, C.; Tanner, E.; Bonfield, W. In vitro and in vivo evaluation of polyhydroxy butyrate and of polyhydroxybutyrate reinforced with hydroxyapatite. 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Claims

CLAIMS1. A biodegradable polymer blend comprising:poly(L-lactic acid) (PLLA);a polylactide comprising lactate units having the configuration of D-lactic acid and lactate units having the configuration of L-lactic acid (DL-polylactide); andpoly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV).

2. The polymer blend of claim 1 , wherein the DL-polylactide is poly(L-lactide-co-D,L-lactide) (PLDL).

3. The polymer blend of claim 1 or claim 2, wherein the blend comprises up to 50 wt% DL-polylactide.

4. The polymer blend of any preceding claim, wherein the blend comprises at least 1 wt% DL-polylactide.

5. The polymer blend of any preceding claim, wherein the blend comprises from 5 to 25 wt% DL-polylactide.

6. The polymer blend of any preceding claim, wherein the blend comprises up to 90 wt% PLLA.

7. The polymer blend of any preceding claim, wherein the blend comprises at least 40 wt% PLLA.

8. The polymer blend of any preceding claim, wherein the blend comprises from 65 to 85 wt% PLLA.

9. The polymer blend of any preceding claim, wherein the blend comprises up to 15 wt% PHBV.

10. The polymer blend of any preceding claim, wherein the blend comprises at least 1 wt% PHBV.

11. The polymer blend of any preceding claim, wherein the blend comprises from 2.5 to 10 wt% PHBV.

12. The polymer blend of any preceding claim, wherein the blend comprises polycaprolactone (PCL).

13. The polymer blend of claim 12, wherein the blend comprises up to 12.5 wt% PCL.

14. The polymer blend of claim 12 or claim 13, wherein the blend comprises at least 1 wt% PCL, optionally wherein the blend comprises at least 2.5 wt% PCL.

15. The polymer blend of claim 1 comprising:from 65 to 85 wt% PLLA;from 7.5 to 20 wt% PLDL;from 2.5 to 12.5wt% PCL; andfrom 1 to 10wt% PHBV.

16. A polymer composite comprising: the polymer blend of any preceding claim; and an additive.

17. The polymer composite of claim 16, wherein the additive comprises a bioceramic.

18. The polymer composite of claim 17, wherein the bioceramic comprises hydroxyapatite; and / or a mesoporous bioactive glass, optionally wherein the hydroxyapatite is nanohydroxyapatite19. The polymer composite of anyone of claims 16 to 18, wherein the composite comprises up to 10 wt% of the additive.

20. An implant comprising the polymer blend of anyone of claims 1 to 15 or the polymer composite of any one of claims 16 to 19.

21. The implant of claim 20, wherein the implant is an orthopaedic fixation implant, optionally wherein the orthopaedic fixation implant is a fracture fixation plate.

22. A process for forming a polymer blend of any one of claims 1 to 15, the process comprising blending PLLA, DL-polylactide, and PHBV to form the polymer blend.

23. A process for forming a polymer composite of any one of claims 16 to 19, the process comprising blending PLLA, DL-polylactide, PHBV and the additive to form the polymer composite.

24. The process of claim 22 or 23, wherein the blending is carried out using a twin screw extruder.

25. A process for forming an implant of claim 20 or claim 21 , the process comprising forming the implant from the polymer blend of anyone of claims 1 to 15 or the polymer composite of any one of claims 16 to 19, optionally wherein the process comprises 3D printing the implant from the polymer blend of any one of claims 1 to 15 or from the polymer composite of any one of claims 16 to 19.

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