Additively manufactured porous polymeric medical implants

Abstract

An article comprising a multilayer polyaryletherketone (PAEK), wherein each layer is comprised of a continuous length of PAEK, wherein the continuous length of PAEK in at least one layer comprises an interior and an outer surface comprising a crystalline region, wherein the crystallinity of the outer surface is higher than the crystallinity of the interior. The cross-sectional area of the continuous length of PAEK is non-uniform within each layer. Each layer defines a plane, and a portion of the continuous length of PAEK in each layer extends beyond the plane defined by the layer. The multilayer PAEK defines a network of interconnected pores.

Description

[0001] Claiming priority

[0002] This application claims priority to U.S. Patent Application Serial No. 63 / 429,746, filed December 2, 2022, and U.S. Patent Application Serial No. 63 / 329,209, filed April 8, 2022, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] Medical implants are devices placed inside the body to replace or support biological structures such as bones. Summary of the Invention

[0004] In a first aspect, an article comprising multilayered polyaryletherketone (PAEK) is included, wherein each layer consists of a continuous length of PAEK, wherein at least one layer of the continuous length of PAEK comprises: an interior and an outer surface including crystalline regions, wherein the crystallinity of the outer surface is higher than that of the interior. The cross-sectional area of ​​the continuous length of PAEK is non-uniform within each layer, or each layer defines a plane and a portion of the continuous length of PAEK in each layer extends beyond the plane defined by that layer, or both. The multilayered PAEK defines a network of interconnected pores.

[0005] Each implementation scheme may include one or any combination of two or more of the following features.

[0006] In each layer, continuous lengths of PAEK are arranged in aligned rows. In some cases, the rows have a serpentine, curved, or zigzag configuration. In some cases, rows in each layer are rotated relative to rows in adjacent layers. In some cases, rows in each layer are rotated 20-60° relative to rows in adjacent layers. In some cases, rows in each layer are rotated 36° relative to rows in adjacent layers.

[0007] The cross-sectional area of ​​a continuous PAEK is not uniform within each layer.

[0008] A continuous length of PAEK extends between adjacent layers.

[0009] Each layer defines a plane, and a portion of a continuous length of PAEK in each layer extends beyond the plane defined by that layer.

[0010] A continuous length of PAEK in each layer intersects with a continuous length of PAEK in the adjacent layer at the node. In some cases, the continuous length of PAEK extending between adjacent nodes is non-linear.

[0011] The outer surface of a continuous length PAAK includes crystalline domains separated by amorphous regions.

[0012] The outer surface of continuous-length PAEK comprises lamellar surface microstructures. In some cases, these lamellar surface microstructures have a characteristic dimension of 4–6 nm. In other cases, the lamellar surface microstructures form spherules on the outer surface of continuous-length PAEK. In some cases, these spherules have a characteristic dimension of 4–6 μm.

[0013] The continuous length of PAEK in the first layer of a multilayer structure has a different degree of crystallinity than the continuous length of PAEK in the second layer of a multilayer structure.

[0014] Multi-layered PAEK defines a trabecular structure.

[0015] Multilayer PAEK forms a triple-periodic minimal surface (TPMS) structure that defines a network of interconnecting vias. In some cases, multilayer PAEK forms a TPMS diamond structure.

[0016] The surface roughness of continuous length PAEK is between 0.5 μm and 3.0 μm, for example, between 1 μm and 1.5 μm.

[0017] The Young's modulus of the product is between 0.3 GPa and 4.0 GPa, for example, between 0.8 GPa and 1.5 GPa.

[0018] The compressive strength of the product is at least 20 kN, for example, between 20 kN and 150 kN, between 20 kN and 100 kN, or between 20 kN and 30 kN.

[0019] The fatigue strength of the product, measured after 5 million cycles at 5Hz, is between 1200N and 1800N.

[0020] The stiffness of the product is between 0.8 GPa and 1.5 GPa.

[0021] The article comprises a coating containing hydroxyapatite disposed on the outer surface of a continuous length of PAEK. In some cases, the thickness of the coating is between 1 nm and 80 nm, for example, between 1 nm and 50 nm or between 1 nm and 20 nm.

[0022] The crystallinity of continuous length PAEK is between 20 vol% and 60 vol%, for example, between 30 vol% and 50 vol%.

[0023] The porosity of the product is 40-80%.

[0024] The pore size is 100μm-1mm, for example, between 100μm and 700μm.

[0025] The average size of the pores is 220-280 μm.

[0026] PAEK includes polyetheretherketone (PEEK).

[0027] The multilayered PAEK defines a first region having a first porosity and a second region having a second porosity different from the first porosity, wherein both the first and second regions span at least some of the layers in the multilayer. In some cases, the PAEK extends continuously between the first and second regions.

[0028] Continuous length PAEK is deposited using additive manufacturing methods such as fused strand fabrication.

[0029] Products include medical implants. In some cases, medical implants are bone-conductive. In some cases, they are osteointegrative. In some cases, they are osteogenic.

[0030] In a second aspect that can be combined with the first aspect, the medical implant includes a multilayer of PAEK deposited by fused wire fabrication, wherein each layer consists of a continuous length of PAEK arranged in aligned rows, and wherein the continuous length of PAEK extends between adjacent layers, wherein the continuous length of PAEK in at least one layer includes: an interior and an outer surface including crystalline regions, wherein the crystallinity of the outer surface is higher than that of the interior, and the cross-sectional area of ​​the continuous length of PAEK is non-uniform within each row; wherein the rows in each layer are rotated relative to the rows in each adjacent layer to form a TPMS diamond structure defining a network of interconnecting holes, such that the porosity of the medical implant is 50-70%, and wherein the medical implant is osteoconductive.

[0031] Each implementation scheme may include one or any combination of two or more of the following features.

[0032] Medical implants include cervical spine implants.

[0033] Medical implants include posterior lumbar interbody fusion implants, transforaminal lumbar interbody fusion implants, anterior lumbar interbody fusion implants, or direct lateral interbody fusion implants.

[0034] Medical implants include joint implants.

[0035] In a third aspect that can be combined with the first and second aspects, the medical implant is produced by a process comprising: extruding PAEK filaments from a nozzle of an additive manufacturing tool to deposit each layer of a multilayer of PAEK, wherein each layer consists of a continuous length of PAEK; and annealing the deposited multilayers to induce crystallization of regions on the outer surface of the continuous length of PAEK, wherein the crystallinity of the outer surface of the continuous length of PAEK is higher than that of the interior, wherein the multilayer of PAEK defines a network of interconnecting holes.

[0036] Each implementation scheme may include one or any combination of two or more of the following features.

[0037] Extruded PAEK filaments consist of aligned rows of PAEK forming a continuous length in each layer.

[0038] The process involves continuously extruding PAEK filaments to form adjacent layers, such that continuous lengths of PAEK extend between adjacent layers.

[0039] The process involves extruding PAEK filaments such that each layer defines a plane, and such that a portion of a continuous length of PAEK extends beyond the plane defined by the layer.

[0040] The process involves extruding PAEK filaments such that continuous lengths of PAEK in each layer intersect with continuous lengths of PAEK in adjacent layers at the nodes. In some cases, the continuous lengths of PAEK extending between adjacent nodes are non-linear.

[0041] The process involves extruding PAEK filaments so that the continuous length of PAEK has a non-uniform cross-sectional area within each layer.

[0042] This process involves extruding PAEK filaments to form a three-period minimal surface (TPMS) structure that defines a network of interconnected vias across multiple layers. In some cases, the multiple layers form a TPMS diamond structure.

[0043] The process involves rotating the additive manufacturing tool after each layer of PAEK has been deposited. In some cases, the process involves rotating the additive manufacturing tool 20–60° after each layer has been deposited.

[0044] The process involves heating the nozzle of the manufacturing tool to a temperature between 325-475°C, for example, to a temperature between 400-450°C.

[0045] Extruding PAEK filaments involves depositing the first layer onto a heated platform.

[0046] The process involves extruding PAEK filaments at an extrusion flow rate of 10-15 mm / s.

[0047] The process involves moving the nozzle relative to the deposited layer at a feed rate of 5-15 mm / s.

[0048] The process involves extruding PAEK filaments at an extrusion ratio of 0.5–4.0, where the extrusion ratio is the ratio between the PAEK extrusion flow rate and the nozzle travel speed relative to the deposited layer. In some cases, the extrusion ratio is 0.5–2.0, for example, 0.6–1.0.

[0049] The process involves annealing the deposited multilayer at a temperature below the glass transition temperature of PAEK. In some cases, annealing the deposited multilayer involves forming layered surface microstructures on the outer surface of a continuous length of PAEK.

[0050] The process involves applying a coating containing hydroxyapatite to the outer surface of a continuous length of PAEK. In some cases, the coating is applied by dip coating, immersion coating, or spraying.

[0051] The process involves extruding PAEK filaments using a fused strand deposition process.

[0052] The process involves extruding PAEK filaments using a fused filament fabrication process.

[0053] The process involves extruding PAEK filaments using a fused melt deposition process.

[0054] The process involves extruding PAEK filaments to form a first region having a first porosity and a second region having a second porosity different from the first porosity, wherein both the first and second regions span at least some of the layers in a multilayer. In some cases, a continuous length of PAEK extends between the first and second regions.

[0055] The methods described herein can possess one or more of the following advantages. The porous PAEK medical implants described herein possess mechanical properties comparable to those of physiological bone, such as strength and modulus. Furthermore, the porous PAEK medical implants described herein are bioactive, exhibiting osteogenic behaviors (e.g., osteoconduction, osteointegration, and immunomodulation (osteoinduction)). When implanted in a subject, porous PAEK medical implants with this combination of mechanical and biological properties promote rapid and durable bone growth.

[0056] Details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features and advantages will become apparent from the specification, drawings, and claims. Attached Figure Description

[0057] Figure 1 This is a photo of a porous PAEK medical implant.

[0058] Figure 2A and Figure 2B This is a diagram of the layers of a porous PAEK medical implant.

[0059] Figure 3A and Figure 3B This is an optical image of a porous PAEK medical implant.

[0060] Figure 4A and Figure 4B These are scanning electron microscope (SEM) images of porous PAEK medical implants.

[0061] Figure 5A and Figure 5B This is a SEM image of a porous PAEK medical implant.

[0062] Figure 6A and Figure 6B This is a SEM image of a porous PAEK medical implant.

[0063] Figure 7 This is a picture of a porous PAEK medical implant.

[0064] Figures 8A-8D This is a photo of a porous PAEK medical implant.

[0065] Figure 9A and Figure 9B This is a photo of a porous PAEK medical implant.

[0066] Figure 10 This is a diagram of the components of an additive manufacturing system.

[0067] Figures 11A-11C This is the result of the compression test.

[0068] Figures 12A-12B It is the result of mechanical testing.

[0069] Figure 13 It is a testing process.

[0070] Figures 14-16 This is a graph showing the results of human bone marrow stromal cells (hBMSC) assay.

[0071] Figure 17 It is a testing process.

[0072] Figures 18-21 This is a graph showing the results of macrophage assays.

[0073] Figure 22- Figure 28 It is a histological image.

[0074] Figure 29 Including micro-computed tomography images. Detailed Implementation

[0075] We describe here the additive manufacturing of medical implants using polyaryletherketone (PAEK), for example, by fused deposition of PAEK. The resulting medical implants have a sparse lattice structure defining a network of interconnecting holes and mimic the structure of physiological (e.g., trabecular) bone. The PAEK strands of the implant have a semi-amorphous interior and an outer surface with crystalline domains, the outer surface providing a surface roughness that also mimics the physiological environment. The cross-sectional area of ​​the PAEK strands in the implant is non-uniform and non-linear, for example, such that the PAEK strands in one layer have an attenuated profile extending into the underlying layer.

[0076] These porous PAEK medical implants exhibit mechanical properties comparable to or better than those of physiological bone, such as strength and modulus. Furthermore, these porous PAEK medical implants are bioactive, exhibiting behaviors related to osteoconduction, osteointegration, osteogenic formation, and immune modulation.

[0077] refer to Figure 1 The medical implant 100 is a porous structure formed from multiple additively manufactured layers of polyaryletherketone (PAEK) thermoplastic, such as polyetherketone (PEK), polyetheretherketone (PEEK), polyetherketoneketone (PEKK), polyetheretherketoneketone (PEEKK), or polyetherketoneetherketoneketone (PEKEKK). Each PAEK layer consists of one or more continuous lengths of PAEK. The continuous lengths of PAEK are strands of PAEK deposited by continuously (e.g., without interruption) extruding PAEK from an additive manufacturing tool. Figure 1 In the example, more than one consecutive length of PAEK in each layer is set with aligned line 102 (see also...). Figures 2A-2B However, in some instances, continuous lengths of PAEK are configured differently. Continuous lengths of PAEK define the network of interconnect holes 104. Figure 1 The medical implant 100 is a cervical spine implant; however, other types of bone implants may have similar structures and compositions.

[0078] Medical implant 100 has osteogenic potential. For example, the medical implant is osteoconductive, meaning that osteocytes can grow on the surface of the medical implant. Medical implant 100 is also osseointegrative, meaning that a direct structural connection can be formed between the bone and the implant 100, such as a connection that cannot be separated in the absence of fracture. Furthermore, medical implant 100 is immunomodulatory (e.g., has osteoinductive potential), meaning that the medical implant can induce osteogenesis, for example, by recruiting immature cells and stimulating those cells to develop into pre-osteoblasts. For example, within a period of approximately 4–12 weeks after implantation in a living body, substantially all (e.g., greater than 90% or greater than 95%) of the pore volume of medical implant 100 is filled with viable natural bone. Without being bound by theory, it is believed that the surface microstructure, pore structure, and composition of the medical implant contribute to the osteogenic (e.g., osteoconductive, osseointegrative, and immunomodulatory / osteoinductive) behavior of medical implant 100, as discussed in more detail below.

[0079] Osteointegration can be characterized in various ways, including through histological bone deposition and histological bone quality, physiological bone quality, biomechanical bone quality, the quality of the bone-implant interface, and bone durability (e.g., lifespan). Osteogenesis (e.g., immune modulation) can be characterized by macrophage polarization arrays that indicate regenerative behavior, such as through muscle pouch implantation. Osteogenesis can be characterized by cell differentiation and gene expression.

[0080] As described below, the porous PAEK medical implant described herein has a substantially periodic lattice structure defining a network of interconnected pores. This structure enables the medical implant to possess high compressive strength, elastic modulus, and toughness. The interconnectedness of the pores and the pore size distribution contribute to the osteogenic behavior of the medical implant.

[0081] The surface microstructures of porous PAEK medical implants described herein contribute to their physiological behavior. For example, surface crystallinity and surface roughness achieved through fused wire deposition manufacturing processes toughen PAEK and make its surface hydrophilic, mimicking physiological biomechanics and promoting osteogenic formation. Surface microstructures, such as nano-textured crystallinity, also mimic physiological bone and contribute to osteogenic behaviors (e.g., osteoconduction, osteointegration, and immune modulation (e.g., osteoinduction)).

[0082] Figure 2AThis is a schematic diagram of a single layer 200 of a porous PAEK medical implant. Layer 200 consists of two consecutive lengths of PAEK 202, 204 arranged in aligned rows 206, each consecutive length of PAEK 202, 204 extending between adjacent rows. In some instances, each layer of the medical implant consists of a single consecutive length of PAEK, and in some instances, each layer of the medical implant includes multiple consecutive lengths of PAEK.

[0083] Rows 206 are spaced apart such that layer 200 is sparsely filled with material, for example, such that less than 50%, for example less than 30%, or less than 25% of the total area of ​​the layer is occupied by PAEK material. For example, the width w of the PAEK material in each row... r Between 75μm and 400μm, and adjacent rows are separated by width w g Gap separation between 50μm and 500μm. Figure 2A The rows 202 of layer 200 have a serpentine structure, but in some instances, the rows have other structures, such as zigzag, curved, sinusoidal, or straight lines. In some instances, more than one consecutive length of PAEK in layer 200 is randomly arranged.

[0084] Porous PAEK medical implants consist of multiple layers stacked on top of each other. Figure 2B It shows Figure 2A Layer 200, wherein a second layer 210 is disposed above layer 200. Each layer 200, 210 consists of, for example, one or more consecutive lengths of PAEK arranged in aligned rows, as per [reference to...]. Figure 2A As discussed, in some instances, continuous lengths of PAEK extend between adjacent layers 200 and 210, thereby connecting these two layers. Subsequent layers may have similar structures, such that continuous lengths of PAEK extend between at least some pairs of adjacent layers in the medical implant.

[0085] The orientation of each row in a layer defines the orientation of that layer. In medical implants, the orientation of each layer differs from that of adjacent layers; for example, rows in one layer are rotated relative to rows in adjacent layers. The orientations of layers 200 and 210 are indicated by arrows 208 and 218, respectively. Typically, rows in a medical implant are rotated between 20° and 60° relative to rows in adjacent layers, for example, between 20° and 40° or between 30° and 40°, for example, approximately 36°. Figure 2A In the example, the rows of layer 200 are rotated approximately 30° relative to the rows of layer 210.

[0086] A continuous length of PAEK in each layer (e.g., in layer 200) contacts a continuous length of PAEK in an adjacent layer (e.g., in layer 210) at a node (e.g., node 220). The PAEK in the upper layer 210 is supported at node 220 by the PAEK in the lower layer 200, but portions of the continuous length of PAEK extending between adjacent nodes are not supported by the lower layer. Due to the sparse structure and relative rotation of the layers, and due to the time and temperature distribution of the manufacturing process, as discussed further below, at least some unsupported portions of the continuous length of PAEK in a given layer droop from the plane defined by that layer and toward the plane defined by the lower layer, e.g., defining a nonlinear connection between nodes. For example, the unsupported portion of the PAEK drooping from one layer to the lower layer extends into the plane of the lower layer by an amount of up to about 50% of the height of the lower layer, e.g., between 10% and 30% or between 25% and 50%. In a specific instance, when layers 200 and 210 each have a height of approximately 200 μm, the unsupported portion of PAEK extends from the upper layer 210 into the plane of the lower layer at a distance between 75 μm and 100 μm.

[0087] The time and temperature distribution of the manufacturing process also results in a non-uniform cross-sectional diameter or area within each layer of a continuous length of PAEK. For example, the diameter or cross-sectional area of ​​a continuous length of PAEK at or near a node can be larger than that of the same continuous length of PAEK extending between nodes. In various examples, the cross-sectional area of ​​the narrowest portion of the attenuation length of the PAEK (e.g., near the midpoint between nodes) is 10%–50% smaller than that of the widest portion (e.g., at or near a node), for example, 20%–40%, 10%–25%, or 25%–50%.

[0088] In some instances, a PAEK of more than one continuous length extends between adjacent nodes in a medical implant; for example, the extrusion of the PAEK is interrupted at each node. In some instances, a PAEK of more than one continuous length spans multiple nodes in each row of a given layer; for example, some or all nodes extend. In some instances, a PAEK of more than one continuous length extends across multiple rows (e.g., as...). Figure 2A (As shown). A continuous length of PAEK in a given medical implant can all have the same length or can have different lengths.

[0089] Figure 3A and Figure 3B It is a photo of a porous PEEK medical implant, and Figure 4A and Figure 4BThese are scanning electron micrographs of porous PEEK medical implants. These images reveal the sparse porous structure of the medical implants and the nonlinear and inhomogeneous properties of PEEK over continuous lengths between adjacent nodes. The textured surface of the PEEK is also shown in these images, which will be discussed in more detail below.

[0090] like Figures 3A-3B and Figures 4A-4B As shown, the continuous length of PAEK constituting the porous PAEK medical implant forms a substantially periodic lattice structure defining a network of interconnecting holes 300. The substantially periodic lattice structure is a structure composed of repeating units, with slight variations caused by factors such as the manufacturing process. In one example, the layers of PAEK form a three-periodic minimal surface matte (TPMS) lattice structure, such as a TPMS diamond lattice structure, a TPMS gyroid lattice structure, a TPMS linear lattice structure, or a TPMS spherical lattice structure. Figures 3A-3B and Figures 4A-4B In this example, layers of PAEK can form a TPMS diamond lattice structure that mimics the trabecular structure of bone, thus providing a strut-like anatomy similar to natural bone. The TPMS lattice structure possesses three-dimensional symmetry and a high surface area to volume ratio. This structure offers biomechanical advantages, such as providing favorable system energy and enabling stress dissipation and strain dispersion. The TPMS lattice structure also offers biological advantages, such as promoting fluid flow and permeability, mimicking the cellular microenvironment (e.g., by providing appropriate oxygen levels), providing high surface area exposure, and promoting osseointegration.

[0091] Porous PAEK medical implants have a porosity between 40% and 80% by volume, for example, about 40%, about 50%, about 60%, about 70%, or about 80%. Interconnecting pores are pores accessible from the outside of the medical implant. The average size (e.g., diameter) of the pores 300 is between 50 μm and 1 mm, for example, between 100 μm and 700 μm, between 100 μm and 500 μm, between 200 μm and 300 μm, or between 220 μm and 280 μm. In some cases, the pores are irregularly shaped, such as non-spherical. For example, when the lattice structure of the medical implant is a TPMS diamond lattice structure, the pores are essentially diamond-shaped. The pore size and porosity of the porous PAEK medical implants described herein mimic the architecture of trabecular bone and provide a large surface area for contact between the bone and the medical implant, thereby promoting osteogenesis.

[0092] The crystallinity of PAEK in porous PAEK medical implants varies between the interior and exterior of the material. For example, in at least some locations of a PAEK medical implant, the crystallinity of the outer surface of a continuous length of PAEK is greater than that of the interior of the continuous length of PAEK. In specific instances, the crystallinity of the interior of at least some continuous lengths of PAEK in a PAEK medical implant is less than 50% by crystal volume, for example, between 10% and 50%, between 20% and 40%, or between 25% and 35% by crystal volume. The internal crystallinity is low enough that the interior appears translucent during imaging, for example, exhibiting a translucent brown band. The outer surface of these continuous lengths of PAEK includes crystalline domains interspersed with amorphous regions. The crystallinity of the outer surface is higher than that of the interior, for example, between 10% and 50% by surface area. The semi-crystalline outer surface makes the surface appear opaque, for example, having a light beige color. Unbound by theory, it is believed that processing conditions (e.g., the time and temperature distribution of the manufacturing process) can form PAEK with a continuous length of semi-amorphous interior and crystalline outer surface.

[0093] Crystalline domains on the outer surface of a continuous length of PAEK have layered surface microstructures. For example, crystalline domain 506 comprises plate-like, typically hexagonal crystals with characteristic dimensions (e.g., thickness) between 4 nm and 10 nm, such as 6–10 nm, or about 5 nm, and in-plane dimensions (e.g., length or diameter) between 200 nm and 500 nm, such as 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, or 500 nm. Multiple such layered crystals aggregate to form individual crystalline domains. For example, a crystalline domain can be a small sphere with radial microstructure and dimensions (e.g., diameter) between 4 μm and 10 μm, such as between 4 μm and 8 μm or between 4 μm and 6 μm.

[0094] Figure 5A and Figure 5B This is a SEM image of a portion of a continuous length of PEEK in a medical implant, showing the radial microstructure of microspheres forming crystalline domains, where amorphous regions on the outer surface separate the radial arms of the microspheres.

[0095] The microstructure of the outer surface of continuous-length PAEK provides surface roughness (e.g., root mean square (RMS) surface roughness) between 0.5 μm and 3.0 μm, for example, between 1 μm and 1.5 μm. Unbound by theory, it is believed that this surface microstructure (e.g., crystalline domains separated by amorphous regions, and the resulting surface roughness) mimics the surface microstructure of bone, thereby promoting osteogenesis.

[0096] In some instances, the relative crystallinity of the internal and external surfaces of PAEK in porous PAEK medical implants varies with location within the implant. PAEK in layers formed early in the additive manufacturing process (e.g., the bottom layer of the implant during orientation in an additive manufacturing system, referred to as a lower layer) can have a different amount and structure of crystallinity than PAEK in subsequent layers (e.g., the upper layer of the implant, referred to as a higher layer). This difference in crystallinity is optically visible, for example, in thin-section optical microscopic images of PAEK medical imaging (e.g., those obtained for histological imaging). In transmitted light optical images, essentially amorphous regions of PAEK appear translucent, while more crystalline regions appear opaque. In some instances, a gradient of crystallinity exists within the more crystalline, opaque regions.

[0097] It is believed that the greater amount of thermal cycling experienced by lower layers compared to higher layers contributes to this difference in microstructure. Lower layers of medical implants form before higher layers, and therefore experience more thermal cycling than higher layers. This difference in the amount of thermal cycling experienced by layers at different locations within a medical implant contributes to the differences in the microstructure of PAEK.

[0098] In the higher layers, PAEK is deposited at temperatures close to its glass transition temperature. Following deposition, the outer surface of the PAEK cools rapidly, solidifying the unorganized polymer chain arrangement. The interior of the PAEK cools more slowly than the outer surface, allowing for a more organized crystalline structure to form internally. A similar cooling process occurs in the lower layers. However, when an upper layer is deposited on top of an existing lower layer, the PAEK in these lower layers undergoes additional thermal cycling. At the junction of the upper and lower layers, the newly deposited layer remelts the outer surface of the lower layer. The material previously on the outer surface at the junction becomes part of the interior of the PAEK at the junction and cools more slowly, thus becoming more crystalline. Furthermore, other outer surfaces of the lower layers of PAEK are also reheated by the deposition of the upper layers, promoting the reorganization of polymer chains on the outer surfaces and increasing their crystallinity.

[0099] Due to these differences in thermal cycling, the PAEK in the lower layers of a porous PAEK medical implant can have a higher percentage of crystallinity than the PAEK in the higher layers; for example, there may be a crystallinity gradient from one side of the medical implant to the other. Other orientations of the crystallinity gradient may also be achieved, depending on the manufacturing process. For example, a porous PAEK medical implant may have a crystallinity gradient extending from the internal region of the implant to the external region of the implant.

[0100] Furthermore, each individual length of PAEK also exhibits a gradient of crystallinity. Some lengths of PAEK (e.g., in later-deposited layers) have a gradient from the more crystalline interior to the less crystalline outer surface (e.g., due to relatively rapid cooling of the outer surface). Other lengths of PAEK (e.g., in earlier-deposited layers) have a gradient of increasing crystallinity from the interior to the outer surface, for example, because the remelting of these layers provides time for the remodeling of the outer surface. In some instances, post-deposition annealing can further increase the crystallinity of the outer surface of PAEK of various lengths.

[0101] In some instances, the outer surface of continuous lengths of PAEK in porous PAEK medical implants is coated with a coating, such as a hydroxyapatite (HA) coating, a tricalcium phosphate coating, or a calcium phosphate coating. The coating is a crystalline coating that extends throughout the porous structure of the medical implant, essentially covering all outer surfaces of the PAEK. The coating is chemically bonded to the PAEK. Like uncoated PAEK, at least some continuous lengths of the coated PAEK outer surface in porous PAEK medical implants have crystalline regions separated by amorphous domains and exhibit a higher degree of crystallinity than the interior of the same continuous length of PAEK.

[0102] The coating is a thin coating, thin enough that the bone can be directly anchored to the outer surface of the PAEK in the medical implant. Enabling the bone to anchor directly to the PAEK, rather than to the coating itself, provides mechanical stability. For example, the coating thickness is between 1 nm and 80 nm, such as between 1 nm and 50 nm, between 1 nm and 20 nm, or between 1 nm and 10 nm.

[0103] Figure 6A and Figure 6B These are SEM images of PEEK medical implants with an HA coating. As these images show, the HA coating is a crystalline coating with elongated needle-like crystals of length between 50 nm and 250 nm, for example, between 50 nm and 100 nm.

[0104] Certain structural features of porous PAEK medical implants, including the network of interconnected pores, pore size distribution, and the presence of bioactive components (e.g., HA coatings or other bioactive coatings, such as tricalcium phosphate or calcium phosphate coatings), contribute to the osteoconductive behavior of porous PAEK medical implants. Bioactive components also contribute to the bone-stimulating behavior of the medical implants. Microscopic and nanostructural features, including surface crystallinity and surface roughness, contribute to the bone-inducing (e.g., immunomodulatory) behavior of the medical implants.

[0105] In some instances, porous PAEK medical implants have multiple regions, each with a different porosity. For example, see reference... Figure 7The porous PAEK medical implant 900 includes a first region 902 with high porosity, for example, a porosity between 40% and 80%; and a second region 908 with much lower porosity, for example, a porosity between 0% and 10%. Figure 7 In some instances, regions 902 and 908 both span all layers of the porous PAEK medical implant (e.g., from the bottom to the top of the implant), but in some instances, more than one of the multiple regions does not span all layers. In some instances, a continuous length of PAEK connects two regions 902 and 908 in at least one layer, meaning, for example, that the extrusion of that length of PAEK will not be interrupted even when regions with different porosities begin to be printed.

[0106] The porous PAEK medical implants described herein can be configured for use in a variety of anatomical settings. Figure 1 The porous PAEK medical implant is a cervical spine implant. (Reference) Figures 8A-8D Other types of spinal implants can be porous PAEK medical implants, including posterior lumbar interbody fusion implants (PLIF, see below). Figure 8A Transforaminal lumbar interbody fusion implant (TLIF, see below) Figure 8B ), anterior lumbar interbody fusion implant (ALIF, see Figure 8C ), direct lateral intercondylar fusion implant (DLIF, see Figure 8D Or, a far lateral intercondylar fusion implant (XLIF). (See reference) Figure 9A and Figure 9B Porous PAEK medical implants can be used for implants in the limbs. Figure 9A ), such as tibial plateau implants, cotton implants, or Evans wedge implants, or implants for large joints ( Figure 9B The medical implants described herein may also be cranial implants or maxillofacial implants, or may be used for the reconstruction of bones such as internal bones, foot or ankle bones, hand or wrist bones, or other suitable bones.

[0107] Porous PAEK structures can be used in other medical applications, such as drug delivery or neurological applications. Porous PAEK structures can also be configured for non-medical environments. For example, porous PAEK structures can be used in aerospace applications, such as aircraft engine components (e.g., due to their high heat resistance and performance at high temperatures), aircraft exterior components (e.g., due to their resistance to rain corrosion), or other aerospace applications (e.g., as a substitute for aluminum due to their light weight); automotive applications; or other suitable environments.

[0108] While we refer to porous PAEK structures here, these porous additive manufacturing structures can also be formed from other materials, including polycaprolactone (PCL), poly(L-lactide) (PLLA), poly(glycolic acid) (PGA), polysulfone (PSF), or other polymers. In some instances, these porous additive manufacturing structures can be composite materials, such as polymer composites, like layered polymer composites. They can contain ceramics or slurries, biological agents, cellular materials, or proteins.

[0109] The porous PAEK structures (e.g., medical implants) described herein possess mechanical properties suitable for the environments in which the structure is used. For example, the mechanical properties of porous PAEK medical implants are comparable to those of the physiological bone at the target implantation site. Unless otherwise stated, the mechanical properties described herein are measured according to ASTM F2077 testing standards.

[0110] The Young's modulus of the porous PAEK structure described herein is between 0.3 GPa and 4.0 GPa, for example, between 0.3 GPa and 3.0 GPa, between 0.8 GPa and 1.5 GPa, or between 1.0 GPa and 1.2 GPa. This range of Young's modulus is comparable to that of cancellous bone.

[0111] The compressive strength of the porous PAEK structure is at least 20 kN, for example, between 20 kN and 150 kN, between 20 kN and 100 kN, between 20 kN and 40 kN, or between 22 kN and 30 kN. The compressive strength in this range is significantly higher than that of physiological bone (e.g., compressed cancellous bone), for example, at least two times or at least six times higher, for example, 2 to 10 times higher.

[0112] The porous PAEK structure described herein exhibits fatigue strength between 1200 N and 1800 N, for example, 1500 N, under 5 million cycles at 5 Hz. The stiffness of the porous PAEK structure described herein is between 0.8 GPa and 1.5 GPa, for example, between 1.0 GPa and 1.2 GPa.

[0113] Other mechanical properties of porous PAEK structures, such as torque, compression-shear, and sedimentation, are comparable to those of the physiological bone at the target implantation site.

[0114] Unbound by theory, it is believed that the crystalline microstructure of the porous PAEK structures described herein (where the semi-amorphous interior is enclosed within a crystalline outer surface) contributes to these mechanical properties. For example, the crystallization of the outer surface that occurs during the cooling of the PAEK after printing (discussed further below) produces a surface compression layer that imparts strength and stiffness to PAEKs of various lengths and thus to the structure as a whole. Furthermore, porous lattice structures, such as TPMS diamond structures with interconnected porosity, also contribute to the strength, modulus, and toughness of the structure.

[0115] refer to Figure 10 The porous PAEK medical implants described herein are manufactured using additive manufacturing systems that perform additive manufacturing processes such as filament deposition, filament fabrication, or molten metal deposition. As mentioned above, the time and temperature distribution of the additive manufacturing process contributes to the nonlinear and non-uniform properties of the PAEK constituting the continuous length of the medical implant, as well as the surface microstructure of the PAEK.

[0116] The system includes a printhead 252 for heating and dispensing printing material, such as PAEK filament, from nozzles 260 of the printhead 252 onto a build plate 290. The filament is supplied via inlet 264 to a supply tube 262 of the printhead 252, which is connected via an internal channel 268 to an outlet 266 of the supply tube. The internal channel 268 of the supply tube 262 has an upstream portion 270 and a downstream portion 272. As the PAEK filament passes through the downstream portion 272 of the supply tube 262, a heater 256 heats the filament to a temperature significantly higher than the melting point of PAEK, for example, 50-100°C above the melting point. For example, the heater 256 heats the filament to a temperature between 325°C and 475°C. In a particular instance, when the filament is PEEK with a melting point of approximately 340°C, the heater 256 heats the filament to a temperature between 400°C and 500°C, for example, between 400°C and 450°C, such as 430°C. As discussed further below, heating PAEK to a temperature significantly above its melting point allows the extruded PAEK to remain molten immediately upon deposition, which contributes to the aforementioned nonlinear and non-uniform porous structure.

[0117] The upstream portion 270 of the supply tube 262 is cooled by a cooler 254 to regulate the temperature of the PAEK filament as it passes through the supply tube 262. The cooler 254 is spaced upstream from the heater 256, with a gap 276 separating the cooler 254 from the heater 256. In some instances, a secondary cooler 278 directly cools the PAEK filament in the supply tube 262.

[0118] Hot zone 280 isolates the heat generated by heater 256 from the cooler temperatures in the areas of cooler 254 and secondary cooler 278. The presence of hot zone 280 allows the PAEK filament to remain solid until it reaches hot zone 280, at which point it begins to transition from a solid to a molten state. This configuration prevents the heat from heater 256 from melting the PAEK filament in the upstream portion 270 of the supply tube, which could lead to premature crystallization of the PAEK.

[0119] Molten PAEK filaments are extruded through nozzle 260 onto a build plate 290 to form a porous PAEK structure. The build plate 290 rotates relative to nozzle 260 between the formation of each successive layer of PAEK, for example, between 20° and 60°, between 20° and 40°, or between 30° and 40°, for example, approximately 36°. This rotation, along with the sparse filling of each layer, means that a large amount of PAEK in the upper layers is unsupported by the lower layers. This unsupported porous structure, along with the temperature distribution during extrusion, contributes to the microstructure of the resulting porous PAEK structure.

[0120] The extrusion speed of the PAEK filaments from nozzle 260 and the speed at which nozzle 260 moves relative to the building plate 290 during extrusion (referred to as the feed rate) also affect the microstructure of the resulting porous PAEK structure. For example, for nozzle diameters between 0.2 mm and 0.5 mm, the PAEK extrusion speed can be between 2 mm / s and 20 mm / s, for example, between 10 mm / s and 15 mm / s. The feed rate can be between 5 mm / s and 20 mm / s, for example, between 8 mm / s and 12 mm / s or between 10 mm / s and 20 mm / s. Faster extrusion and feed rates both result in thinner PAEK bead deposition.

[0121] The ratio between extrusion speed and feed speed is called the extrusion ratio. Typically, PAEK filaments are extruded at extrusion ratios between 0.5 and 4.0, for example between 0.5 and 2.0, or between 0.6 and 1.0. A smaller extrusion ratio (e.g., a lower extrusion speed for the same feed speed) results in a thinner bead deposition, which can manifest as attenuation (e.g., nonlinear and non-uniform diameter) in the unsupported portions of the deposited PAEK.

[0122] For example, the microstructure of the porous PAEK structure may undergo localized changes due to the extrusion path. For instance, as the extrusion path moves from one row to another around a corner, the extruded PAEK experiences acceleration and deceleration, resulting in bulges on the upstream side of the corner and attenuation on the downstream side. These microstructural changes provide the resulting porous PAEK structure with micrometer-level roughness, mimicking the microstructure of physiological bone.

[0123] The printed plane and the PAEK structure on it are maintained at a temperature around the glass transition temperature of PAEK, for example, between 130°C and 160°C. In some instances, the temperature of the printed plane is maintained by a reflector 292, which may be made of a material with passive heat reflection properties or may include an active heating element, or both. In some instances, the temperature of the printed plane is maintained by a heating layer disposed below the build plate 290 (e.g., on the side of the build plate 290 opposite to the print head 252). In some instances, both a reflector and a heating layer are used. The operation of the reflector 292, the heating layer, or both can be controlled via closed-loop feedback control to maintain the printed plane at the target temperature.

[0124] Maintaining the printing plane at a temperature around the glass transition temperature of PAEK keeps the printed PAEK in a glassy state. This, in turn, allows PAEK of various lengths in adjacent layers to bond together. For example, when molten PAEK strands are extruded from nozzle 260 of printhead 252, the molten PAEK remelts the PAEK of the underlying, already printed layer, thereby bonding the two PAEK lengths together and forming a node. Extruding PAEK at a temperature significantly above the melting point of PAEK further promotes this remelting and bonding; the thermally extruded PAEK is held above its melting point for a sufficient time after being extruded from nozzle 810 to allow the underlying PAEK to remelt and bond with it.

[0125] Extruding PAEK at temperatures significantly above its melting point, and maintaining the printed plane at around the glass transition temperature of PAEK, allows for the formation of nonlinear and non-uniform lengths of PAEK between the nodes of the structure. After the extruded PAEK is bonded to the underlying PAEK to form nodes, the molten PAEK stretches across the unsupported space before reaching another PAEK support and forming another node. This attenuation of PAEK between nodes results in non-uniformity in its diameter: PAEK is stretched to a smaller diameter between nodes and retains a larger diameter at the nodes. This stretching of PAEK also causes unsupported, molten, or glassy PAEK to sag into the plane of the underlying layer. It is believed that the stretching of PAEK also leads to bending of unsupported PAEK of various lengths, which further contributes to the surface microstructure of the PAEK.

[0126] Maintaining the printed plane at a temperature around the glass transition temperature of PAEK also contributes to the resulting crystalline structure of PAEK, which has a semi-amorphous interior and an outer surface with crystalline (e.g., layered) microstructures. For example, slow cooling facilitated by prolonged residence at the glass transition temperature allows the outer surface to crystallize. Furthermore, the remelting of the previously extruded PAEK at the nodes during the deposition of the next layer of PAEK further extends the cooling time and contributes to surface crystallization.

[0127] Following the additive manufacturing process, the porous PAEK medical implant is annealed. Annealing is performed at a temperature below the glass transition temperature of PAEK. For example, when the medical implant is made of PEEK with a glass transition temperature of approximately 140°C, the porous PEEK medical implant is annealed for a period of time between 150°C and 300°C, for example, between 150°C and 200°C, for example, for a period of time between 1 hour and 10 hours. After manufacturing, the outer surface of the PAEK in the medical implant has the characteristics described above. Figures 6A-6B The described layered surface microstructure.

[0128] In some instances, a coating, such as a hydroxyapatite coating, is applied to the surface of a porous PAEK medical implant after the additive manufacturing process and annealing. The coating can be applied using coating processes such as dip coating, immersion coating, or spray coating. The coating is applied to all surfaces of the porous PAEK medical implant, for example, extending through the internal porous structure of the implant.

[0129] Example

[0130] Unless otherwise stated, all tests are performed on PEEK articles formed by fused wire under the following parameters.

[0131] Example 1: Mechanical Properties

[0132] The mechanical properties of the PEEK cervical implants manufactured as described above were tested, including compressive strength, elastic modulus, and fatigue strength. Unless otherwise stated, the mechanical properties described herein were measured according to ASTM F2077 testing standards.

[0133] refer to Figure 11A and Figure 11B The compressive strength of PEEK cervical implants was measured using a static axial compression test. See details in the attached document. Figure 11A The study found that the compressive strength of the PEEK cervical implant exceeded 25 kN, which means that the PEEK cervical implant partially failed after a force of 25 kN was applied. Figure 11B This is a photograph of the PEEK cervical implant after a 25kN compressive force was applied, showing that the implant remained largely intact with only partial failure.

[0134] The elastic modulus of the PEEK cervical implant was measured to be 1.0 GPa, which is comparable to that of cancellous bone.

[0135] The fatigue strength of the PEEK cervical implant was measured using a dynamic axial compression test according to ASTM F2077. The PEEK cervical implant withstood 5 million cycles of a 1500 N force applied at 5 Hz and maintained structural integrity. Figure 11C This is a photo of the PEEK cervical implant after completing the dynamic axial compression test.

[0136] The stiffness of the PEEK cervical implant was determined during static axial compression testing. The PEEK cervical implant was measured at Kd = 13,623 N / mm (approximately the 75th percentile of FDA published data).

[0137] Further mechanical testing was conducted on the porous PEEK cervical interbody fusion cage without radiographic markers to confirm that the observed mechanical properties were due to the PEEK structure rather than radiographic markers.

[0138] Dynamic axial compression testing was performed on PEEK cervical intervertebral disc implants without radiographic markers. Figure 12A Showing photos of the implant before testing. Figure 12B Photographs of the implants after 500,000 cycles are shown. As the photographs indicate, the dynamic axial compression test caused virtually no mechanical damage. Table 1 shows the height measurements for each of the two samples, confirming that the implants maintained structural integrity.

[0139]

[0140] Table 1. Dynamic axial compression test height measurements of PEEK implants without radiographic markers after 5,000,000 cycles.

[0141] Drop hammer clinical impact testing was also performed on PEEK cervical intervertebral disc implants without radiographic markers. The samples were tested according to the test parameters listed in Table 2.

[0142] sample Impact energy (J) Speed ​​(m / s) Falling height (m) Number of impacts 1 1.54 1.41 0.10 4 2 3.08 1.99 0.20 2 3 4.62 2.43 0.30 1 4 6.16 2.81 0.40 1

[0143] Table 2. Drop hammer clinical impact test parameters

[0144] The drop-weight test results shown in Table 3 indicate that the implant maintained structural integrity:

[0145]

[0146] Table 3. Results of Drop Hammer Clinical Impact Tests

[0147] Example 2: Biological activity of porous PEEK structures

[0148] Regarding osteogenicity of human bone marrow stromal cells (hBMSCs), the osteogenic potential of PEEK cervical implants with various microstructures and surface chemistry properties was characterized. This assay determines whether hBMSCs transform into osteoblasts, i.e., bone-forming cells, upon exposure to a specific surface. This transformation is primarily demonstrated by surface cell markers and the resulting gene expression and protein production. Materials demonstrating this cellular transformation are considered to possess osteogenic potential. As illustrated in this example, the porous PEEK cervical implant demonstrated osteogenic potential in this assay.

[0149] Figure 13 The assay procedure is illustrated. On day 0 of the assay, hBMSCs were plated onto four substrates: tissue culture polystyrene (TCPS) as a control, porous PEEK cervical implants (PP) fabricated as described above, porous PEEK cervical implants with HA coating (PP-HA), and solid PEEK blocks (SP). Cells were cultured for fourteen days, after which the cultures were exposed to fresh-condition culture medium for 24 hours. Cell layer lysates were extracted and measured, and the results included osteocalcin, osteopontin, osteoprotegerin, vascular endothelial growth factor (VEGF), and DNA. Interleukins including IL-4, IL-10, and IL-6, BMP-2, BMP-4, BgLAP, RUNX-2, and SP7 were also measured.

[0150] Figure 14 The results of hBMSC assays demonstrate the influence of various surface chemistry properties and microstructures on the osteogenic potential of the structure, as shown by protein production, including the concentrations of DNA, osteocalcin, osteopontin, osteoprotein, and vascular endothelial growth factor 165. Figure 15 The study demonstrates the production of interleukins, further illustrating the influence of surface chemistry and microstructure on the osteogenic potential of the structure. Figure 15 The top and bottom rows represent two different experimental runs, which usually show consistent results. (Reference) Figure 16 Furthermore, the above-mentioned hBMSC cultures were analyzed to characterize gene expression, in order to further demonstrate the osteogenic potential of the structure.

[0151] Table 4 provides a summary of the results and their significance.

[0152]

[0153] Table 4. Results of osteogenic potential assay.

[0154] Osteocalcin is a mineralized protein. The presence of osteocalcin indicates the presence of osteoblasts, thus suggesting an environment conducive to bone formation. These results show upregulation of osteocalcin: osteocalcin concentrations in cultures from all three PEEK samples were higher than in TCPS cultures. Osteopontin and osteoprotegerin are proteins that promote bone formation and, in particular, regulate osteoclast upregulation. As shown in these figures, while the concentrations of osteopontin and osteoprotegerin in cultures from all three PEEK samples were higher than in TCPS cultures, porous PEEK (PP) cultures showed significantly higher concentrations of each protein than in the other PEEK samples. Vascular endothelial growth factor (VEGF) contributes to angiogenesis. VEGF concentrations in cultures from all three PEEK samples were higher than in TCPS cultures, with the highest concentrations observed in two porous PEEK cultures (PP and PP-HA). These results are positive indicators of the osteogenic potential of porous PEEK.

[0155] Gene expression results were also a positive indicator of the osteogenic potential of porous PEEK. The last group (BMP-2, BMP-4, BgLAP, Runx2, SP7) were either upregulated or showed no change.

[0156] Overall, the simultaneous upregulation of OCN, OPN, OPG, VEGF, IL-4, and IL-10 with downregulation of IL-6, relative to solid PEEK, demonstrates osteogenic potential in both porous PEEK (PP) and porous PEEK with HA coating (PP-HA). Although different proteins may be expressed at different time points during physiological bone formation, the results of this cellular (in vitro) assay are consistent with the behavior of known bone-forming (osteogenic) materials.

[0157] refer to Figure 17 In another experiment, macrophage polarization assays were performed to characterize the implant's immunomodulatory potential. Macrophage polarization assays validated the response of naive macrophages (e.g., those present in the early stages of inflammation, injury, or surgery) to specific surfaces. M1 macrophages clear debris and trigger pro-inflammatory cytokines, while macrophages that transition to the M2 phenotype are pro-regenerative macrophages. M1 phenotype macrophages exhibit specific gene expression leading to fibrous tissue formation. M2 phenotype macrophages release different proteins leading to pro-regenerative, anti-inflammatory regeneration, thereby contributing to bone formation.

[0158] Indicators of pro-inflammatory M1 macrophages lead to the expression of iNOS, TNF-α, IL-6, and IL-1β. Indicators of pro-regenerative (anti-inflammatory) M2 macrophages lead to the expression of Arg1, Mrc1, TGF-β1, IL-4, and VEGF. As shown below, consistent with this behavior, the upregulation and downregulation of genes and proteins represented by PP and PP-HA surfaces confirm the transition to the M2 phenotype, indicating the immunomodulatory behavior of PP and PP-HA structures.

[0159] At the start of this method, macrophages were harvested and expanded for seven days, during which time the medium was replaced with medium containing macrophage colony-stimulating factor (MCSF). After seven days of macrophage expansion, the macrophages were plated dropwise onto surfaces containing MCSF. Macrophage experiments were then performed. Specifically, two days after plating, the medium was replaced with fresh medium, and five test groups were measured: porous PEEK (PP), porous PEEK with HA coating (PP-HA), solid PEEK (SP), and two control groups treated with M1 and M2, respectively. No MCSF was provided to any of the test groups.

[0160] Results of assays indicating pro-inflammatory responses (e.g., M1 expression) are as follows: Figure 18 As shown, porous PEEK inhibits the M1 inflammatory phase, particularly compared to solid PEEK. Measurements indicating tissue repair response (e.g., M2 expression) are as follows. Figure 19 As shown, porous PEEK promotes M2 expression (promoting regeneration and leading to bone formation). Further measurements were performed seven days after plating. These results are shown in Figures 2019 and 2120 and are generally consistent with... Figure 18 and Figure 19 The results from both days were consistent: porous PEEK inhibited the inflammatory phase and promoted M2 expression.

[0161] These results demonstrate that the upregulation and downregulation of genes and proteins by PP and PP-HA samples lead to macrophage polarization into the pro-regenerative M2 phenotype and the expected gene and protein expression / production. These results also demonstrate the suppression and downregulation of pro-inflammatory genes and proteins in the M1 phenotype.

[0162] These results are generally consistent with the hBMSC assays discussed above: PEEK samples showed markers indicating bone growth to a greater extent than control samples. In summary, these validated cellular assays confirm that porous PEEK manufactured according to the above-described fused-wire process and porous PEEK with an HA coating demonstrate both osteogenic potential and immunomodulatory (immunoelastogenesis) behavior, which is typically uncommon on PEEK surfaces.

[0163] It is noteworthy that the above measurements are favorable for materials known to possess submicron surface morphology, needle-like morphology, and submicron pore size that are hydrophilic and physiologically compatible (e.g., Ca / P chemistry). The porous PEEK implants described herein possess these characteristics. Specifically, these results demonstrate that even porous PEEK implants without an HA coating possess sufficient properties (e.g., properties imparted by the filament manufacturing process) to provide positive results in these measurements.

[0164] The aforementioned osteogenic assay was performed as follows. Human female MSCs (23-year-old Caucasian) were cultured to confluence in MSC growth medium (GM) before being plated onto the test surface. Test plates from each group were loaded with 0.5 mL of MSCs at 10,000 cells / cm² per well. 2 Cells were plated at a density of 20,000 cells / mL / well in 24-well plates. After 24 hours of plating, the medium was replaced with GM, and subsequent GM replacements were made every 48 hours until day 14. At the start of day 14, the medium was replaced with fresh GM, and the cells were incubated for 24 hours prior to harvest. At harvest, the medium was collected and aliquoted into 1.5 mL Eppendorf centrifuge tubes. The wells containing MSCs were rinsed twice with 1 mL of phosphate-buffered saline (PBS), placed in 0.5 mL of 0.05% Triton-X100, and frozen at -80°C for bioassays.

[0165] To analyze DNA content, cell layers were lysed by sonication at 40V for 10 seconds per well, and total DNA content was determined by fluorescence. Protein and cytokine production levels in the conditioned medium were quantified using enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's protocol. Proteins analyzed included osteocalcin (OCN), osteoprotegerin (OPG), bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 4 (BMP4), bone morphogenetic protein 7 (BMP7), interleukin-6 (IL6), interleukin-4 (IL4), and interleukin-10 (IL10).

[0166] Following the experimental protocol below, macrophages derived from primary immature bone marrow were used to characterize macrophage polarization responses to various implants.

[0167] Immature macrophages were cultured for 1 and 3 days on TCPS, porous PEEK (PP), porous PEEK with hydroxyapatite (PP-HA), and solid PEEK (SP) in RPMI basal medium supplemented with 10% fetal bovine serum (FBS), 1% penicillin / streptomycin (Pen / Strep), and 30 ng / mL macrophage colony-stimulating factor (M-CSF). These cultures were compared with M1- and M2-induced macrophage phenotypes. M1 was induced by supplementing the growth medium with interferon-γ (IFN-γ) and lipopolysaccharide (LPS), while M2 was induced using IL-4 / IL-13. M1- and M2-induced macrophages were compared with immature macrophages cultured on surface materials. The secreted inflammatory markers TNFα, IL-1, IL-4, IL-6, IL-10, and IL-13 were quantified in response to the implant material. To determine the gene expression of inducible nitric oxide synthase (iNOS), a marker of the M1 phenotype, and arginine-1 (Arg1), a marker of the M2 phenotype.

[0168] Bone marrow harvesting was performed as follows. Primary mouse macrophages were isolated from the femurs of 6-8 week old male C57BL / 6 mice. Bone marrow cells were washed from the mouse femurs using Dulbecco's phosphate-buffered saline. Red blood cells were lysed from the bone marrow extract using ACK lysis buffer. Cells were collected and pooled to produce a mixed population of mouse cells. Cells were counted and seeded at a density of 500,000 cells / mL in 10 mL RPMI 1640 medium supplemented with 10% FBS, 50 U / mL penicillin-50 μg / mL streptomycin, and 30 ng / mL macrophage colony-stimulating factor in 75 cm⁻¹ plates. 2 Above. Cells were cultured at 37°C, 5% CO2, and 100% humidity. Seven days after plating to produce a homogeneous population of immature macrophages, macrophages were passaged using Accutase at a density of 20,000 cells / cm². 2 The density is used to inoculate it onto the designated surface.

[0169] For surface plating, PP, PP-HA, and SP samples were washed and irradiated with gamma rays. Immature macrophages were plated on the surface in RPMI 1640 medium with 30 ng / mL LM-CSF, and the macrophage phenotypes induced by M1 and M2 plating on TCPS were compared. The M1 phenotype was induced by supplementing the growth medium with IFN-γ (20 ng / mL) and LPS (100 ng / mL) at plating time. M2 was induced by using IL-4 / IL-13 (20 ng / mL each) at plating time. Macrophages were planted at a density of 10,000 cells / cm². 2The cells were seeded at a density of 20,000 cells / mL / well on the surface of a 24-well plate. The plate was replaced with RPMI 1640 containing M-CSF 24 hours before harvest.

[0170] After 24 hours of treatment, the conditioned medium was collected and aliquoted into 1.5 mL Eppendorf centrifuge tubes. The wells were rinsed twice with 1 mL PBS and aspirated. 1 mL of 0.05% Triton-X was added and the mixture was incubated overnight at -20°C. The secreted inflammatory markers TNFα, IL1β, IL4, IL6, IL10, and IL13 were quantified by ELISA in response to the surface, according to the manufacturer's protocol. The immunoassay results were normalized to the dsDNA content in the cell lysates. The culture medium was analyzed by ELISA according to the manufacturer's protocol.

[0171] For PCR harvest, cells were lysed and homogenized in QiaZol for separation using a centrifuge column. Cell monolayers were washed in PBS, lysed in 0.05% Triton X-100, and homogenized by sonication at 40V for 10 seconds per well. RNAeasy centrifuge columns were run according to the manufacturer's instructions and quantification was performed using a Take3 spectrometer (Qiagen). mRNA levels of iNos (M1) and Arg1 (M2) were measured and normalized to Gapdh.

[0172] Example 3: Live animal testing of porous PEEK implants

[0173] Various types of PEEK implants, including porous PEEK implants, porous PEEK implants with HA coating, and solid PEEK implants, were implanted into older female sheep (4-5 years old). The implants had an outer diameter of 25 mm × 6 mm. Bone growth at the bone-implant interface was evaluated at 4 and 12 weeks post-surgery. Surface characterization of the implants was performed using optical microscopy and scanning electron microscopy prior to implantation. The mechanical properties of the implants in the cortical and cancellous bone sites, as well as in the cortical bone site, were evaluated over time by radiography. New bone formation was evaluated over time based on routine PMMA histology in the cortical and cancellous sites.

[0174] The implants were press-fitted into the cancellous bone of the distal femur and proximal tibia, and then placed in the cortical bone of the tibia in a line-to-line manner. Samples were examined at 4 and 12 weeks post-surgery using standard shear stress push-out tests, as well as histological and morphological examinations.

[0175] At designated time points, each animal was euthanized and examined and dissected according to SOP-28. The right and left hind limbs were harvested, photographed, and radiographed. The tibia and femur were scanned using a Siemens Inveon Micro CT to provide high-resolution scans of the bone-implant interface and to assess any osseointegration. The cancellous tissue was dissected and fixed in cold phosphate-buffered formalin. The cortical tissue was dissected and sectioned in the sagittal plane to separate medial and lateral samples for ejection testing.

[0176] Immediately after separation, cortical and cancellous tissue samples were processed for PMMA histological analysis. Following SOP-24, samples were placed in 10% buffered formalin and subsequently dehydrated in ethanol of increasing concentrations for embedding in polymethyl methacrylate (PMMA). Following SOP-35, the embedded cortical and cancellous tissue implants were sectioned along the long axis of the implant using a Leica SP 1600 microtome. At least two thin (15–20 μm) sections were cut from each embedded implant and stained with methylene blue and basic fuchsin, resulting in bone staining pink and fibrous tissue staining blue or purple.

[0177] Figure 22A and Figure 22B Includes histological images showing the implantation of a porous PEEK implant with an HA coating 4 weeks prior. See reference for details. Figure 22B In the image of the implant, the lighter translucent band indicates that PEEK is amorphous, while the opaque area is crystalline. Figure 23 This includes histological images showing implantation 12 weeks post-implantation. These images demonstrate bone infiltration and osseointegration throughout the implant, proving its effectiveness in promoting osteoconduction, osseointegration, and osteogenic formation.

[0178] Figure 24 Additional images include histological findings 12 weeks after implantation of a porous PEEK implant with an HA coating. These images show the layering of PEEK within the implant itself: the shallower, translucent bands are amorphous regions, while the opaque regions are crystalline. Cortical bone, typically stained purple, has grown through the implant without significant fibrous tissue growth. Blood vessels, such as those formed by epithelial cells, are present and allow the supply of bone marrow, blood, etc., to the bone. Osteoblasts and osteocytes are also present, indicating healthy new bone growth.

[0179] Figure 25A and Figure 25B Including porous PEEK implants with HA coating ( Figure 25A ) and porous PEEK implants without HA coating ( Figure 25B Histological images of implanted in different animals 12 weeks later. These images show new bone growth throughout the porous structure of both implants.

[0180] Figure 26 This is a 12-week histological image of a porous PEEK implant without HA coating, implanted at the metaphysis. The image shows cancellous bone growth throughout the porous structure of the implant.

[0181] Figures 27-28 These are 12-week histological images of porous PAEK implants from sheep, showing the quality of bone formation within the implant. Figure 27 Including transmitted light images and Figure 28 This includes stereomicroscopic images. These images demonstrate the formation of bone structures within the implant, such as blood vessels, osteocytes, and ring bone formation.

[0182] Figure 29 These are micro-computed tomography (micro-CT) images taken 12 weeks after implantation of a porous PEEK implant with an HA coating. These images demonstrate bone growth around and throughout the implant. For example, the lateral and medial sides of the bone where boreholes were drilled to insert the implant show healed bone growth. Specifically, white areas, such as area 60, are primary cortical bone, while gray areas, such as area 62, are new bone growth. These images also show bone growth throughout the pores of the implant: the implant is dark, while the bone throughout the porous structure of the implant is white.

[0183] In embodiment 1, the article comprises a multilayer polyaryletherketone (PAEK), wherein each layer consists of a continuous length of PAEK, and at least one continuous length of PAEK in a layer includes an interior and an outer surface comprising crystalline regions, wherein the crystallinity of the outer surface is higher than that of the interior. The cross-sectional area of ​​the continuous length of PAEK is non-uniform within each layer, or each layer defines a plane and a portion of the continuous length of PAEK in each layer extends beyond the plane defined by that layer, or both. The multilayer of PAEK defines a network of interconnecting vias.

[0184] In Implementation 2, which can be combined with Implementation 1, continuous lengths of PAEK in each layer are arranged in aligned rows.

[0185] In implementation scheme 3, which can be combined with implementation scheme 2, the row has a serpentine, curved, or zigzag structure.

[0186] In implementation scheme 4, which can be combined with any of implementation schemes 2 or 3, rows in each layer are rotated relative to rows in adjacent layers.

[0187] In Implementation Scheme 5, which can be combined with Implementation Scheme 4, rows in each layer are rotated 20-60° relative to rows in adjacent layers.

[0188] In Implementation Scheme 6, which can be combined with Implementation Scheme 5, rows in each layer are rotated 36° relative to rows in adjacent layers.

[0189] In embodiment 7, which can be combined with any of the aforementioned embodiments, the cross-sectional area of ​​the continuous length of PAEK is non-uniform within each layer.

[0190] In embodiment 8, which can be combined with any of the aforementioned embodiments, a continuous length of PAEK extends between adjacent layers.

[0191] In embodiment 9, which can be combined with any of the foregoing embodiments, each layer defines a plane, and a portion of a continuous length of PAEK in each layer extends beyond the plane defined by that layer.

[0192] In embodiment 10, which can be combined with any of the aforementioned embodiments, a continuous length of PAEK in each layer intersects with a continuous length of PAEK in the adjacent layer at a node.

[0193] In embodiment 11, which can be combined with embodiment 10, the continuous length of PAEK extending between adjacent nodes is non-linear.

[0194] In embodiment 12, which can be combined with any of the foregoing embodiments, the outer surface of the continuous length PAAK includes crystalline domains separated by amorphous regions.

[0195] In embodiment 13, which can be combined with any of the foregoing embodiments, the outer surface of the continuous length of PAEK includes a layered surface microstructure.

[0196] In embodiment 14, which can be combined with embodiment 13, the layered surface microstructure has a feature size of 4-6 nm.

[0197] In embodiment 15, which can be combined with embodiment 14, layered surface microstructures form small spheres on the outer surface of a continuous length of PAEK.

[0198] In embodiment 16, which can be combined with embodiment 15, the microsphere has a characteristic size of 4-6 μm.

[0199] In embodiment 17, which can be combined with any of the aforementioned embodiments, the continuous length of PAEK in the first set of multilayers has a different degree of crystallinity than the continuous length of PAEK in the second set of multilayers.

[0200] In embodiment 18, which can be combined with any of the aforementioned embodiments, the multi-layered PAEK defines a small beam structure.

[0201] In embodiment 19, which can be combined with any of the aforementioned embodiments, the multilayer PAEK forms a three-period minimal surface (TPMS) structure that defines a network of interconnect holes.

[0202] In embodiment 20, which can be combined with embodiment 19, multilayer PAEK forms a TPMS diamond structure.

[0203] In embodiment 21, which can be combined with any of the foregoing embodiments, the surface roughness of the continuous length of PAEK is between 0.5 μm and 3.0 μm.

[0204] In embodiment 22, which can be combined with embodiment 21, the surface roughness of the continuous length of PAEK is between 1 μm and 1.5 μm.

[0205] In embodiment 23, which can be combined with any of the aforementioned embodiments, the Young's modulus of the article is between 0.3 GPa and 4.0 GPa.

[0206] In embodiment 24, which can be combined with embodiment 23, the Young's modulus of the article is between 0.8 GPa and 1.5 GPa.

[0207] In embodiment 25, which can be combined with any of the aforementioned embodiments, the compressive strength of the article is at least 20 kN.

[0208] In embodiment 26, which can be combined with embodiment 25, the compressive strength of the article is between 20 kN and 150 kN.

[0209] In embodiment 27, which can be combined with embodiment 26, the compressive strength of the article is between 20 kN and 100 kN.

[0210] In embodiment 28, which can be combined with embodiment 27, the compressive strength of the article is between 20 kN and 30 kN.

[0211] In embodiment 29, which can be combined with any of the aforementioned embodiments, the fatigue strength of the article is measured to be between 1200N and 1800N after 5 million cycles at 5Hz.

[0212] In embodiment 30, which can be combined with any of the aforementioned embodiments, the stiffness of the article is between 0.8 GPa and 1.5 GPa.

[0213] In embodiment 31, which can be combined with any of the foregoing embodiments, the article includes a hydroxyapatite-containing coating disposed on the outer surface of a continuous length of PAEK.

[0214] In embodiment 32, which can be combined with embodiment 31, the coating thickness is between 1 nm and 80 nm.

[0215] In embodiment 33, which can be combined with embodiment 32, the coating thickness is between 1 nm and 50 nm.

[0216] In embodiment 34, which can be combined with embodiment 33, the coating thickness is between 1 nm and 20 nm.

[0217] In embodiment 35, which can be combined with any of the foregoing embodiments, the crystallinity of the continuous length of PAEK is between 20 vol% and 60 vol%.

[0218] In embodiment 36, which can be combined with embodiment 35, the crystallinity of the continuous length of PAEK is between 30 vol% and 50 vol%.

[0219] In embodiment 37, which can be combined with any of the aforementioned embodiments, the porosity of the article is 40-80%.

[0220] In embodiment 38, which can be combined with any of the aforementioned embodiments, the pore size is 100 μm-1 mm.

[0221] In embodiment 39, which can be combined with embodiment 38, the pore size is between 100 μm and 700 μm.

[0222] In embodiment 40, which can be combined with any of the foregoing embodiments, the average size of the pores is 220-280 μm.

[0223] In embodiment 41, which can be combined with any of the foregoing embodiments, PAEK includes polyether ether ketone (PEEK).

[0224] In embodiment 42, which can be combined with any of the foregoing embodiments, the multilayer PAEK defines a first region having a first porosity and a second region having a second porosity different from the first porosity, and both the first region and the second region span at least some of the multilayers.

[0225] In embodiment 43, which can be combined with embodiment 42, the continuous length of PAEK extends between the first and second regions.

[0226] In embodiment 44, which can be combined with any of the foregoing embodiments, continuous lengths of PAEK are deposited by additive manufacturing.

[0227] In embodiment 45, which can be combined with embodiment 44, continuous lengths of PAEK are deposited by filament fabrication.

[0228] In embodiment 46, which can be combined with any of the aforementioned embodiments, the article includes a medical implant.

[0229] In implementation scheme 47, which can be combined with implementation scheme 46, the medical implant is bone-conductive.

[0230] In implementation scheme 48, which can be combined with any of implementation schemes 46 to 47, the medical implant is osseointegrated.

[0231] In implementation scheme 49, which can be combined with any of implementation schemes 46 to 48, the medical implant is osteogenic.

[0232] In embodiment 51, the medical implant includes a multilayer of PAEK deposited by fused wire fabrication, wherein each layer consists of a continuous length of PAEK arranged in aligned rows, and wherein the continuous length of PAEK extends between adjacent layers, wherein at least one layer of the continuous length of PAEK includes: an interior and an outer surface including crystalline regions, wherein the crystallinity of the outer surface is higher than that of the interior, and the cross-sectional area of ​​the continuous length of PAEK is non-uniform within each row; wherein the rows in each layer are rotated relative to the rows in each adjacent layer to form a TPMS diamond structure defining a network of interconnecting holes, such that the porosity of the medical implant is 50-70%, and wherein the medical implant is osteoconductive.

[0233] In embodiment 52, which can be combined with embodiment 51, the medical implant includes a cervical spine implant.

[0234] In embodiment 53, which can be combined with any of embodiments 51 to 52, the medical implant includes a posterior lumbar interbody fusion implant, a transforaminal lumbar interbody fusion implant, an anterior lumbar interbody fusion implant, or a direct lateral interbody fusion implant.

[0235] In embodiment 54, which can be combined with any of embodiments 51 to 53, the medical implant includes a joint implant.

[0236] In implementation scheme 55, the medical implant is manufactured through a process including the following:

[0237] PAEK filaments are extruded from the nozzle of an additive manufacturing tool to deposit each layer of a multilayered PAEK, wherein each layer consists of a continuous length of PAEK; and

[0238] The deposited multilayers are annealed to induce crystallization in regions of the outer surface of the continuous-length PAEK, where the crystallinity of the outer surface of the continuous-length PAEK is higher than that of the interior.

[0239] The multi-layered PAEK defines the network of interconnect holes.

[0240] In embodiment 56, which can be combined with embodiment 55, the process includes extruding PAEK filaments, wherein the extrusion of PAEK filaments includes forming aligned rows of PAEK of continuous length in each layer.

[0241] In embodiment 57, which can be combined with any of embodiments 55 to 56, the process includes continuously extruding PAEK filaments to form adjacent layers such that a continuous length of PAEK extends between adjacent layers.

[0242] In embodiment 58, which can be combined with any of embodiments 55 to 57, the process includes extruding filaments of PAEK such that each layer defines a plane, and such that a portion of a continuous length of PAEK extends beyond the plane defined by the layer.

[0243] In embodiment 59, which can be combined with any of embodiments 55 to 58, the process includes extruding PAEK filaments such that continuous lengths of PAEK in each layer intersect with continuous lengths of PAEK in adjacent layers at nodes.

[0244] In embodiment 60, which can be combined with embodiment 59, the continuous length of PAEK extending between adjacent nodes is non-linear.

[0245] In embodiment 61, which can be combined with any of embodiments 55 to 60, the process includes extruding PAEK filaments such that the continuous length of PAEK has a non-uniform cross-sectional area within each layer.

[0246] In embodiment 62, which can be combined with any of embodiments 55 to 61, the process includes extruding PAEK filaments such that multiple layers form a three-period minimal surface (TPMS) structure that defines a network of interconnecting holes.

[0247] In embodiment 63, which can be combined with embodiment 62, a multilayer TPMS diamond structure is formed.

[0248] In embodiment 64, which can be combined with any of embodiments 55 to 63, the process includes rotating the additive manufacturing tool after depositing each layer of PAEK.

[0249] In embodiment 65, which can be combined with embodiment 64, the process includes rotating the additive manufacturing tool 20-60° after each layer is deposited.

[0250] In embodiment 66, which can be combined with any of embodiments 55 to 65, the process includes heating the nozzle of the manufacturing tool to a temperature of 325-475°C.

[0251] In embodiment 67, which can be combined with embodiment 66, the process includes heating the nozzle to a temperature of 400-450°C.

[0252] In embodiment 68, which can be combined with any of embodiments 55 to 67, extruding PAEK filaments includes depositing a first layer onto a heated platform.

[0253] In embodiment 69, which can be combined with any of embodiments 55 to 68, the process includes extruding PAEK filaments at an extrusion flow rate of 10-15 mm / s.

[0254] In embodiment 70, which can be combined with any of embodiments 55 to 69, the process includes moving the nozzle relative to the deposited layer at a feed rate of 5-15 mm / s.

[0255] In embodiment 71, which can be combined with any of embodiments 55 to 57, the process includes extruding PAEK filaments at an extrusion ratio of 0.5-4.0, where the extrusion ratio is the ratio between the extrusion flow rate of PAEK and the movement speed of the nozzle relative to the deposited layer.

[0256] In embodiment 72, which can be combined with embodiment 71, the filament of PAEK is extruded at an extrusion ratio of 0.5-2.0.

[0257] In embodiment 73, which can be combined with embodiment 72, it includes extruding PAEK filaments at an extrusion ratio of 0.6-1.0.

[0258] In embodiment 74, which can be combined with any of embodiments 55 to 73, the process includes annealing the deposited multilayer at a temperature below the glass transition temperature of PAEK.

[0259] In embodiment 75, which can be combined with embodiment 74, annealing the deposited multilayer includes forming layered surface microstructures on the outer surface of a continuous length of PAEK.

[0260] In embodiment 76, which can be combined with any of embodiments 55 to 75, the process includes applying a coating containing hydroxyapatite to the outer surface of a continuous length of PAEK.

[0261] In embodiment 77, which can be combined with embodiment 76, applying the coating includes applying the coating by dip coating, immersion coating, or spray coating.

[0262] In embodiment 78, which can be combined with any of embodiments 55 to 77, the process includes extruding PAEK filaments using a melt deposition process.

[0263] In embodiment 79, which can be combined with any of embodiments 55 to 77, the process includes extruding PAEK filaments using a melt-filament manufacturing process.

[0264] In embodiment 80, which can be combined with any of embodiments 55 to 77, the process includes extruding PAEK filaments using a melt deposition process.

[0265] In embodiment 81, which can be combined with any of embodiments 55 to 80, the process includes extruding a filament of PAEK to form a first region having a first porosity and a second region having a second porosity different from the first porosity, wherein both the first region and the second region span at least some of the multilayers.

[0266] In embodiment 82, which can be combined with embodiment 81, the continuous length of PAEK extends between the first and second regions.

[0267] Specific embodiments of the subject matter have been described. Other embodiments are within the scope of the appended claims.

Claims

1. An article comprising: A multilayer polyaryletherketone (PAEK) wherein each layer is composed of continuous strands of PAEK, wherein at least one layer comprises: Inside, and The outer surface includes the crystalline region, wherein the crystallinity of the outer surface is higher than that of the interior. The cross-sectional area of ​​the PAEK in the continuous strands is non-uniform within each layer, and The multilayered PAEK defines a network of interconnect holes.

2. The article of claim 1, wherein the PAEK of the continuous strands in each layer is arranged in aligned rows, and wherein the rows in each layer are rotated relative to the rows in the adjacent layers.

3. The article of claim 2, wherein the rows in each layer are rotated 20-60° relative to the rows in the adjacent layers.

4. The article of claim 1, wherein the continuous strands of PAEK extend between adjacent layers.

5. The article of claim 1, wherein each layer defines a plane, and wherein a portion of the PAEK of the continuous strands in each layer extends beyond the plane defined by the layer.

6. The article of claim 1, wherein the PAEK of the continuous strand in each layer intersects with the PAEK of the continuous strand in the adjacent layer at the nodes, and wherein the PAEK of the continuous strand extending between adjacent nodes is non-linear.

7. The article of claim 1, wherein the outer surface of the continuous strand PAEK includes crystalline domains separated by amorphous regions.

8. The article of claim 1, wherein the outer surface of the PAEK of the continuous strand comprises a layered surface microstructure, wherein the layered surface microstructure has a feature size of 4-6 nm.

9. The article of claim 8, wherein the layered surface microstructure forms microspheres on the outer surface of the continuous strand PAEK, wherein the microspheres have a characteristic size of 4-6 μm.

10. The article of claim 1, wherein the PAEK of the continuous strands in the first group of layers of the multilayer has a different degree of crystallinity than the PAEK of the continuous strands in the second group of layers of the multilayer.

11. The article of claim 1, wherein the multilayered PAEK defines a small beam structure.

12. The article of claim 1, wherein the multilayer PAEK forms a three-period minimal surface (TPMS) structure defining a network of interconnecting vias.

13. The article of claim 1, wherein the surface roughness of the PAEK of the continuous strand is between 0.5 μm and 3.0 μm.

14. The article of claim 1, wherein the Young's modulus of the article is between 0.3 GPa and 4.0 GPa.

15. The article of claim 1, wherein the compressive strength of the article is at least 20 kN.

16. The article of claim 1, wherein the fatigue strength of the article, measured after 5 million cycles at 5 Hz, is between 1200 N and 1800 N.

17. The article of claim 1, wherein the crystallinity of the continuous strand of PAEK is between 20 vol% and 60 vol%.

18. The article of claim 1, wherein the porosity of the article is 40-80%.

19. The article of claim 1, wherein the article of claim 1 comprises a medical implant, and wherein the medical implant is bone-conductive.

20. The article of claim 1, wherein the article of claim 1 comprises a medical implant, and wherein the medical implant is osseointegrated.

21. The article of claim 1, wherein the article of claim 1 comprises a medical implant, and wherein the medical implant is osteogenic.

22. The article of claim 21, wherein the surface microstructure of the article contributes to osteogenic formation of the article.

23. The article of claim 1, wherein a defined opening extends through the article, the opening extending from a first surface of the article to an opposing second surface, and The article contains a plurality of radiographic markers, each marker extending from a first surface of the article to a second surface.

24. A method comprising: An implantable product in a patient, the product comprising: A multilayer polyaryletherketone (PAEK) wherein each layer is composed of continuous strands of PAEK, wherein at least one layer comprises: Inside, and The outer surface includes the crystalline region, wherein the crystallinity of the outer surface is higher than that of the interior. The cross-sectional area of ​​the PAEK in the continuous strands is non-uniform within each layer, and The multilayered PAEK defines a network of interconnect holes.

25. The method of claim 24, wherein the implanted article is osteogenic.

26. The method of claim 25, wherein the surface microstructure of the article contributes to osteogenic formation of the article.

27. The method of claim 24, wherein the layered surface microstructure of the continuous strand PAEK and the trabecular structure of the multilayer PAEK enable bone cells to enter the implanted article and grow therein.

28. The article of claim 1, wherein the average size of the pores is between 50 μm and 1 mm.

29. The article of claim 28, wherein the average size of the pores is between 220 μm and 280 μm.

30. The article of claim 12, wherein the multilayer PAEK forms a TPMS diamond structure defining a network of interconnecting holes.

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