Additively manufactured porous polymer medical implants

Abstract

An article comprising a plurality of layers of 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 exterior surface comprising crystalline regions wherein the exterior surface has a crystallinity higher than the crystallinity of the interior. The 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 multiple layers of PAEKs define a network of interconnected holes.

Description

[0001] Claiming priority

[0002] This application claims priority to U.S. patent application serial number No. 63 / 429,746 filed on December 2, 2022 and U.S. patent application serial number No. 63 / 329,209 filed on April 8, 2022, the contents of both applications are incorporated herein by reference in their entirety. Background Art

[0003] Medical implants are devices placed into the body to replace or support biological structures, such as bone. Summary of the invention

[0004] In a first aspect, 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 exterior surface comprising a crystalline region, wherein the exterior surface has a higher degree of crystallinity than 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 outside the plane defined by the layer, or both. The multilayer PAEK defines a network of interconnected pores.

[0005] Implementations may include any combination of one or more of the following features.

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

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

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

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

[0010] The continuous length of PAEK in each layer intersects with the 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 the continuous length of PAAK comprises crystalline domains separated by amorphous regions.

[0012] The outer surface of the continuous length of PAEK includes a lamellar surface microstructure. In some cases, the lamellar surface microstructure has a characteristic dimension of 4-6 nm. In some cases, the lamellar surface microstructure forms spherules on the outer surface of the continuous length of PAEK. In some cases, these spherules have a characteristic dimension of 4-6 μm.

[0013] The continuous lengths of PAEK in a first set of layers of the multilayer have a different degree of crystallinity than the continuous lengths of PAEK in a second set of layers of the multilayer.

[0014] The multiple layers of PAEK define a trabecular structure.

[0015] The multiple layers of PAEK form a triply periodic minimal surface (TPMS) structure defining a network of interconnected pores. In some cases, the multiple layers of PAEK form a TPMS diamond structure.

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

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

[0018] The article has a compressive strength of 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 article was measured at 5 Hz for 5 million cycles to be between 1200 N and 1800 N.

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

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

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

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

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

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

[0026] PAEK includes polyetheretherketone (PEEK).

[0027] The multilayer 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 region and the second region span at least some of the multilayers. In some cases, a continuous length of PAEK extends between the first region and the second region.

[0028] Continuous lengths of PAEK are deposited by additive manufacturing such as fused strand fabrication.

[0029] The article includes a medical implant. In some cases, the medical implant is osteoconductive. In some cases, the medical implant is osteointegrative. In some cases, the medical implant is osteogenic.

[0030] In a second aspect that can be combined with the first aspect, a medical implant comprises a plurality of layers of PAEK deposited by fused filament fabrication, wherein each layer is comprised 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 comprises: an interior, and an exterior surface comprising a crystalline region, wherein the crystallinity of the exterior surface is higher than the crystallinity 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 interconnected pores, such that the porosity of the medical implant is 50-70%, and wherein the medical implant is osteoconductive.

[0031] Implementations may include any combination of one or more of the following features.

[0032] Medical implants include cervical spine implants.

[0033] The medical implants include 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.

[0034] Medical implants include joint implants.

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

[0036] Implementations may include any combination of one or more of the following features.

[0037] Extruding filaments of PAEK includes forming aligned rows of continuous lengths of PAEK in each layer.

[0038] The process includes continuously extruding filaments of PAEK to form adjacent layers such that a continuous length of PAEK extends between adjacent layers.

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

[0040] The process includes extruding filaments of PAEK so that a continuous length of PAEK in each layer intersects a continuous length of PAEK in an adjacent layer at a node. In some cases, the continuous length of PAEK extending between adjacent nodes is non-linear.

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

[0042] The process includes extruding filaments of PAEK such that the multiple layers form a tri-periodic minimal surface (TPMS) structure defining a network of interconnected pores. In some cases, the multiple layers form a TPMS diamond structure.

[0043] The process includes rotating the additive manufacturing tool after depositing each layer of PAEK. In some cases, the process includes rotating the additive manufacturing tool 20-60° after depositing each layer.

[0044] The process includes 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 a first layer onto a heated platform.

[0046] The process involves extruding a filament of PAEK 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 speed of 5-15 mm / s.

[0048] The process includes extruding the filaments of PAEK at an extrusion ratio of 0.5-4.0, wherein 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. In some cases, the filaments of PAEK are extruded at an extrusion ratio of 0.5-2.0, for example, at an extrusion ratio of 0.6-1.0.

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

[0050] The process includes disposing a coating comprising hydroxyapatite onto an outer surface of a continuous length of PAEK. In some cases, disposing the coating includes disposing the coating by dip coating, immersion coating, or spray coating.

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

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

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

[0054] 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 multiple layers. In some cases, a continuous length of PAEK extends between the first region and the second region.

[0055] The methods described herein may have one or more of the following advantages. The porous PAEK medical implants described herein have mechanical properties comparable to those of physiological bone, such as strength and modulus, etc. In addition, the porous PAEK medical implants described herein are bioactive, exhibiting osteogenic behavior (e.g., osteoconduction, osteointegration, and immunomodulation (osteoinduction)). When implanted into a subject, the porous PAEK medical implants having this combination of mechanical and biological properties promote rapid and durable bone growth.

[0056] The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

[0060] Figure 4A and Figure 4B is a scanning electron microscope (SEM) image of a porous PAEK medical implant.

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

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

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

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

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

[0066] Fig.10 is a diagram of components of an additive manufacturing system.

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

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

[0069] Fig.13 It is a test process.

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

[0071] Fig.17 It is a test process.

[0072] Figure 18-Figure 21 It is a figure which shows the result of macrophage measurement.

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

[0074] Fig.29 Includes micro-computed tomography images. DETAILED DESCRIPTION

[0075] We describe here a medical implant formed by additive manufacturing of polyaryletherketone (PAEK), for example, by fuse deposition of PAEK. The resulting medical implant has a sparse lattice structure defining a network of interconnected pores and mimics 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 that provide 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 that extends into an 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, etc. In addition, these porous PAEK medical implants are bioactive, exhibiting osteoconductive, osteointegrative, osteogenic, and immunomodulatory behaviors.

[0077] refer to Figure 1 , the medical implant 100 is a porous structure formed by multiple additively manufactured layers of a polyaryletherketone (PAEK) thermoplastic, such as polyetherketone (PEK), polyetheretherketone (PEEK), polyetherketoneketone (PEKK), polyetheretherketoneketone (PEEKK), or polyetherketoneetherketoneketone (PEKEKK). Each layer of PAEK is composed of one or more continuous lengths of PAEK. The continuous length of PAEK is a strand of PAEK deposited by continuously (e.g., without interruption) extruding PAEK from an additive manufacturing tool. Figure 1 In the example of FIG. 1 , more than one continuous length of PAEK in each layer is arranged in aligned rows 102 (see also FIG. 1 ). Figure 2A-2B ); however, in some examples, the continuous length of PAEK is arranged in other configurations. The continuous length of PAEK defines a network of interconnected pores 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 the potential of osteogenic. For example, medical implant is osteoconductive, for example, bone cells can grow on the surface of medical implant. Medical implant 100 is also osseointegrated, meaning that a direct structural connection can be formed between bone and implant 100, for example, a connection that cannot be separated without breaking. In addition, medical implant 100 is immunomodulatory (for example, having the potential of osteoinduction), meaning that medical implant can induce osteogenic, for example, by recruiting immature cells and stimulating those cells to develop into pre-osteoblasts. For example, in a time period of about 4-12 weeks after implantation in a living body, substantially all (for example, 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 medical implant contribute to the osteogenic (for example, osteoconductive, osteointegrated and immunomodulatory / osteoinductive) behavior of medical implant 100, as discussed in more detail below.

[0079] Osseointegration can be characterized in various ways, including by histological bone deposition and histological bone quality, physiological bone quality, biomechanical bone quality, the quality of the bone-implant interface, and the persistence (e.g., longevity) of the skeleton. Osteoinduction (e.g., immunomodulation) can be characterized by polarized arrays of macrophages indicative of regenerative behavior, such as by muscle pocket implantation. Osteogenesis can be characterized by cell differentiation and gene expression.

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

[0081] The surface microstructure of the porous PAEK medical implant described herein contributes to its physiological behavior. For example, the surface crystallinity and surface roughness achieved by the fused filament deposition manufacturing process toughens the PAEK and makes its surface hydrophilic, mimics physiological biomechanics and promotes osteogenesis. The surface microstructure, such as the nano-textured crystallinity of the surface, also simulates physiological bone and contributes to osteogenic behavior (e.g., osteoconduction, osteointegration, and immunomodulation (e.g., osteoinduction).

[0082] Figure 2A2 is a schematic diagram of a single layer 200 of a porous PAEK medical implant. The layer 200 is composed of two continuous lengths of PAEK 202, 204 arranged in aligned rows 206, with each continuous length of PAEK 202, 204 extending between adjacent rows. In some examples, each layer of the medical implant is composed of a single continuous length of PEEK, and in some examples, each layer of the medical implant includes multiple continuous lengths of PEEK.

[0083] The rows 206 are spaced apart so that the layer 200 is sparsely filled with material, for example, so that less than 50%, such as 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 each row of PAEK material is r between 75 μm and 400 μm, and adjacent rows are separated by a width w g Gap separation between 50 μm and 500 μm. Figure 2A The rows 202 of the layer 200 have a serpentine configuration, but in some examples, the rows have other configurations, such as zigzag, curved, sinusoidal, or straight configurations. In some examples, more than one continuous length of PAEK in the layer 200 is randomly arranged.

[0084] The porous PAEK medical implant comprises multiple layers stacked on top of each other. Figure 2B Shows Figure 2A A layer 200 of the embodiment of the present invention, wherein a second layer 210 is disposed above the layer 200. Each layer 200, 210 is composed of, for example, one or more continuous lengths of PAEK arranged in aligned rows, as described with respect to Figure 2A In some examples, a continuous length of PAEK extends between adjacent layers 200, 210, thereby connecting the two layers. Subsequent layers can be similarly constructed such that a continuous length of PAEK extends between at least some adjacent pairs of layers in the medical implant.

[0085] The direction of the rows of each layer defines the orientation of the layer. In the medical implant, the orientation of each layer is different from the orientation of the adjacent layers, for example, the rows of one layer are rotated relative to the rows of each adjacent layer. The orientation of the layers 200, 210 is indicated by arrows 208, 218, respectively. Typically, the rows of one layer of the medical implant are rotated between 20° and 60°, such as between 20° and 40° or between 30° and 40°, such as about 36°, relative to the rows of the adjacent layers. Figure 2A In the example of FIG. 2 , the rows of layer 200 are rotated about 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 by the PAEK in the lower layer 200 at the node 220, but the portion of the continuous length of PAEK extending between adjacent nodes is not supported by the lower layer. Due to the sparse structure and relative rotation of the layers, and due to the time and temperature profile of the manufacturing process discussed further below, at least some of the unsupported portions of the continuous length of PAEK in a given layer sag from the plane defined by the layer and toward the plane defined by the lower layer, e.g., defining a non-linear connection between nodes. For example, the unsupported portion of the PAEK that sags from one layer to the lower layer extends into the plane of the lower layer by an amount 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 example, when the layers 200 , 210 each have a height of approximately 200 μm, the unsupported portion of the PAEK extends from the upper layer 210 into the plane of the lower layer by between 75 μm and 100 μm.

[0087] The time and temperature profile of the manufacturing process also results in a continuous length of PAEK having a non-uniform cross-sectional diameter or cross-sectional area within each layer. For example, the diameter or cross-sectional area of ​​a continuous length of PAEK at or near a node may be larger than the diameter or cross-sectional area of ​​the same continuous length of PAEK in the portion 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 the nodes) is 10%-50% smaller than the cross-sectional area of ​​the widest portion (e.g., at or near the nodes), e.g., 20%-40%, 10%-25%, or 25%-50%.

[0088] In some examples, one or more continuous lengths of PAEK in a medical implant extend between adjacent nodes, e.g., extrusion of the PAEK is interrupted at each node. In some examples, one or more continuous lengths of PAEK extend across multiple nodes, e.g., some or all nodes, in each row of a given layer. In some examples, one or more continuous lengths of PAEK extend across multiple rows (e.g., Figure 2A ). The continuous lengths of PAEK in a given medical implant may all be the same length or may be of different lengths.

[0089] Figure 3A and Figure 3B is a photo of a porous PEEK medical implant, and Figure 4A and Figure 4Bare scanning electron micrographs of porous PEEK medical implants. These images show the sparse porous structure of the medical implant and the nonlinear and inhomogeneous nature of PEEK over a continuous length between adjacent nodes. These images also show the textured surface of PEEK, which will be discussed in more detail below.

[0090] like Figure 3A-3B and Figure 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 interconnected pores 300. A substantially periodic lattice structure is a structure consisting of repeating units with slight variations caused by, for example, the manufacturing process. In one example, the layer of PAEK forms a tri-periodic minimal surface (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. Figure 3A-3B and Figure 4A-4B In an example, a layer of PAEK can form a TPMS diamond lattice structure that simulates the trabecular structure of bone, thereby providing a pillar anatomy similar to natural bone. The TPMS lattice structure has three-dimensional symmetry and a high surface area to volume ratio. The structure has advantages in biomechanics, such as providing favorable system energetics and achieving stress dissipation and strain dispersion. The TPMS lattice structure also has advantages in biology, such as promoting fluid flow and permeability, simulating cell microenvironments (e.g., by providing appropriate oxygen levels), providing high surface area exposure, and promoting bone integration.

[0091] The porous PAEK medical implant has a porosity of between 40% and 80% by volume, such as about 40%, about 50%, about 60%, about 70% or about 80%. Interconnected pores are pores that can be entered from the outside of the medical implant. The average size (e.g., diameter) of the pores 300 is between 50 μm and 1 mm, such as 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 substantially diamond-shaped. The pore size and porosity of the porous PAEK medical implant described herein simulate the architecture of trabecular bone and provide a large amount of surface area for contact between bone and medical implant, thereby promoting osteogenesis.

[0092] The crystallinity of PAEK in a porous PAEK medical implant differs between the interior and exterior of the material. For example, in at least some locations of the PAEK medical implant, the crystallinity of the outer surface of the continuous length of PAEK is greater than the crystallinity of the interior of the continuous length of PAEK. In a specific example, the crystallinity of the interior of at least some continuous lengths of PAEK in the PAEK medical implant is less than 50% by crystalline volume, for example, between 10% and 50%, between 20% and 40%, or between 25% and 35% by crystalline volume. The crystallinity of the interior is low enough that the interior appears translucent when imaged, for example, showing a translucent brown band. The outer surfaces of these continuous lengths of PAEK include crystalline domains with amorphous regions interspersed therebetween. The crystallinity of the outer surface is higher than that of the interior, for example, between 10% and 50% by surface area. The crystallinity of the semi-crystalline outer surface makes the surface appear opaque, for example, having a light beige color. Without being bound by theory, it is believed that the processing conditions (eg, time and temperature profile of the manufacturing process) can form a continuous length of PAEK having a semi-amorphous interior and an outer surface having crystalline regions.

[0093] The crystalline domains on the outer surface of the continuous length of PAEK have a layered surface microstructure. For example, the crystalline domain 506 includes plate-like, generally hexagonal crystals with a characteristic size (e.g., thickness) between 4nm and 10nm, such as 6-10nm, or about 5nm, and an in-plane size (e.g., length or diameter) between 200nm and 500nm, such as 200nm, 250nm, 300nm, 350nm, 400nm, 450nm, or 500nm. A plurality of such layered crystals are gathered together to form each crystalline domain. For example, the crystalline domain can be a sphere having a radial microstructure and a size (e.g., diameter) between 4μm and 10μm, such as between 4μm and 8μm or between 4μm and 6μm.

[0094] Figure 5A and Figure 5B SEM image of a portion of a continuous length of PEEK for a medical implant showing the radial microstructure of globules forming crystalline domains with amorphous regions of the outer surface separating the radial arms of the globules.

[0095] The microstructure of the outer surface of the continuous length of PAEK provides a surface roughness (e.g., root mean square (RMS) surface roughness) between 0.5 μm and 3.0 μm, such as between 1 μm and 1.5 μm. Without being bound 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 interior and exterior surfaces of the PAEK in a porous PAEK medical implant varies with position in the porous PAEK medical implant. The PAEK in a layer formed early in the additive manufacturing process (e.g., the layer at the bottom of the medical implant when oriented in the additive manufacturing system, referred to as the lower layer) can have a different amount and configuration of crystallinity than the PAEK in a subsequent layer (e.g., the layer at the top of the medical implant, referred to as the upper layer). The difference in crystallinity is visible optically, for example, in optical microscope images of thin cross-sections of PAEK medical images (e.g., those obtained for histological imaging). In a transmitted light optical image, substantially amorphous regions of the PAEK appear translucent, while regions of higher crystallinity appear opaque. In some instances, there is a gradient of crystallinity within opaque regions of higher crystallinity.

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

[0098] The PAEK in the higher layers is deposited at a temperature close to the glass transition temperature of the PAEK. After deposition, the outer surface of the PAEK cools rapidly, solidifying the arrangement of the disorganized polymer chains. The interior of the PAEK cools more slowly than the outer surface, allowing a more organized crystalline structure to be produced inside. A similar cooling process occurs for the PAEK in the lower layers. However, when the upper layer is deposited on top of the existing lower layer, the PAEK in these lower layers undergoes additional thermal cycles. At the node where the upper layer contacts the lower layer, the newly deposited layer remelts the outer surface of the lower layer. The material previously on the outer surface at the node becomes the interior of the PAEK at the node and cools more slowly, becoming more crystalline. In addition, the other outer surfaces of the lower layer of the PAEK are also reheated by the deposition of the upper layer, thereby promoting the reorganization of the polymer chains on the outer surface and enabling the crystallinity of the outer surface to increase.

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

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

[0101] In some examples, the outer surface of a continuous length of PAEK in a porous PAEK medical implant 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 through the porous structure of the medical implant, substantially coating all of the outer surface of the PAEK. The coating is chemically bonded to the PAEK. Like uncoated PAEK, the outer surface of at least some continuous lengths of coated PAEK in a porous PAEK medical implant has crystalline regions separated by amorphous domains and has a higher degree of crystallinity than the interior of the same continuous length of PAEK.

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

[0103] Fig. 6A and Figure 6B are SEM images of PEEK medical implants with HA coatings. As shown in these images, the HA coating is a crystalline coating with elongated needle-like crystals with lengths between 50 nm and 250 nm, such as 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 osteostimulatory behavior of medical implants. Micro- and nanostructural features, including surface crystallinity and surface roughness, contribute to the osteoinductive (e.g., immunomodulatory) behavior of medical implants.

[0105] In some examples, a porous PAEK medical implant has multiple regions, each region having a different porosity. Figure 7, the porous PAEK medical implant 900 includes a first region 902 having a high porosity, such as a porosity between 40% and 80%; and a second region 908 having a much lower porosity, such as a porosity between 0% and 10%. Figure 7 In some examples, both regions 902, 908 span all layers of the porous PAEK medical implant (e.g., from the bottom surface to the top surface of the implant), but in some examples one or more of the multiple regions do not span all layers. In some examples, a continuous length of PAEK connects two regions 902, 908 in at least one layer, for example, meaning that extrusion of the length of PAEK is not interrupted even when printing a region of different porosity.

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

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

[0108] Although we refer to porous PAEK structures here, these porous additively manufactured 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 examples, these porous additively manufactured structures can be composite materials, such as polymer composites, such as layered polymer composites. They can contain ceramics or slurries, biologics, cellular materials, or proteins.

[0109] The porous PAEK structures (e.g., medical implants) described herein have mechanical properties suitable for the environment in which the structure is used. For example, the mechanical properties of the porous PAEK medical implants are comparable to the mechanical properties of the physiological bone at the target implant site. Unless otherwise specified, the mechanical properties described herein are measured according to the ASTM F2077 test standard.

[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. The Young's modulus within this range is comparable to that of cancellous bone.

[0111] The compressive strength of the porous PAEK structure is at least 20 kN, such as 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 within this range is significantly higher than the compressive strength of physiological bone (e.g., compressed cancellous bone), such as at least two times or at least six times, such as 2-10 times higher.

[0112] The porous PAEK structure described herein has a fatigue strength of between 1200 N and 1800 N, such as 1500 N, at 5 Hz and 5 million cycles. The porous PAEK structure described herein has a stiffness of between 0.8 GPa and 1.5 GPa, such as between 1.0 GPa and 1.2 GPa.

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

[0114] Without being bound by theory, it is believed that the crystalline microstructure of the porous PAEK structures described herein, in which a semi-amorphous interior is enclosed in a crystalline outer surface, contributes to these mechanical properties. For example, the crystallization of the outer surface that occurs upon cooling of the PAEK after printing (as discussed further below) creates a surface compression layer that imparts strength and stiffness to the various lengths of PAEK and thus the structure as a whole. In addition, the porous lattice structure, such as the TPMS diamond structure with interconnected porosity, also contributes to the strength, modulus and toughness of the structure.

[0115] refer to Fig.10 The porous PAEK medical implants described herein are produced using an additive manufacturing system that implements an additive manufacturing process such as fused filament deposition, fused filament fabrication, or molten melt deposition, etc. As described above, the time and temperature profile of the additive manufacturing process contributes to the nonlinear and inhomogeneous properties of the PAEK that constitutes the continuous length of the medical implant, as well as the surface microstructure of the PAEK.

[0116] The system includes a print head 252 for heating and dispensing a printing material, such as a PAEK filament, from a nozzle 260 of the print head 252 onto a build plate 290. The filament is supplied to a supply tube 262 of the print head 252 via an inlet 264, which is connected to an outlet 266 of the supply tube via an internal channel 268. 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, the heater 256 heats the filament to a temperature significantly higher than the melting point of PAEK, for example, 50-100°C higher than the melting point. For example, the heater 256 heats the filament to a temperature between 325°C and 475°C. In a specific example, when the filament is PEEK having a melting point of about 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, for example, 430°C. As discussed further below, heating the PAEK to a temperature significantly above its melting point allows the extruded PAEK to remain molten immediately upon deposition, which contributes to the non-linear and inhomogeneous porous structure described above.

[0117] An upstream portion 270 of the supply tube 262 is cooled by the cooler 254 to regulate the temperature of the PAEK filaments as they pass 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 examples, a secondary cooler 278 directly cools the PAEK filaments in the supply tube 262.

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

[0119] The molten PAEK filament is extruded through nozzle 260 onto build plate 290 to form a porous PAEK structure. Build plate 290 is rotated relative to nozzle 260 between the formation of each successive layer of PAEK, for example, between 20° and 60°, for example, between 20° and 40° or between 30° and 40°, for example, about 36°. This rotation and the sparse packing of each layer means that a large amount of PAEK in the upper layer is not supported by the lower layer. This unsupported porous structure and the temperature distribution during extrusion contribute to the microstructure of the resulting porous PAEK structure.

[0120] The speed at which the PAEK filament is extruded from the nozzle 260 and the speed at which the nozzle 260 moves relative to the build plate 290 during extrusion (referred to as the feed speed) also affect the microstructure of the resulting porous PAEK structure. For example, for a nozzle diameter between 0.2 mm and 0.5 mm, the extrusion speed of the PAEK can be between 2 mm / s and 20 mm / s, such as between 10 mm / s and 15 mm / s. The feed speed can be between 5 mm / s and 20 mm / s, such as between 8 mm / s and 12 mm / s or between 10 mm / s and 20 mm / s. Faster extrusion speeds and faster feed speeds will result in thinner deposition of the PAEK beads.

[0121] The ratio between the extrusion speed and the feed speed is called the extrusion ratio. Typically, filaments of PAEK are extruded at an extrusion ratio between 0.5 and 4.0, such as 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 thinner deposition of beads, which can exhibit attenuation (e.g., nonlinearity and non-uniform diameter) in the unsupported portion of the deposited PAEK.

[0122] Local changes in the microstructure of the porous PAEK structure may occur, for example, due to the extrusion path. For example, as the extrusion path goes from row to row around a corner, the extruded PAEK undergoes acceleration and deceleration, which results in a bulge on the upstream side of the corner and a decay on the downstream side of the corner. These microstructural changes provide the resulting porous PAEK structure with a micron-scale roughness, such as that of a physiological bone.

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

[0124] Maintaining the print plane at a temperature around the glass transition temperature of PAEK keeps the printed PAEK in its glassy state. This in turn enables bonding between various lengths of PAEK in adjacent layers. For example, as molten PAEK strands are extruded from the nozzle 260 of the print head 252, the molten PAEK remelts the PAEK of the underlying already printed layer, thereby bonding the two lengths of PAEK and forming a node. Extruding PAEK at a temperature significantly above the melting point of PAEK further promotes this remelting and bonding; the hot extruded PAEK is kept above its melting point long enough after being extruded from the nozzle 810 to remelt and bond the underlying PAEK.

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

[0126] Maintaining the print 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 a crystalline (e.g., lamellar) microstructure. For example, slow cooling facilitated by a long dwell at the glass transition temperature enables crystallization of the outer surface. In addition, when the next layer of PAEK is deposited, remelting of previously extruded PAEK at the nodes further extends the cooling time and contributes to surface crystallization.

[0127] After the additive manufacturing process, the porous PAEK medical implant is annealed. The annealing is performed at a temperature below the glass transition temperature of the PAEK. For example, when the medical implant is made of PEEK having a glass transition temperature of about 140°C, the porous PEEK medical implant is annealed at a temperature between 150°C and 300°C, such as between 150°C and 200°C 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 Figure 6A-6B Described layered surface microstructure.

[0128] In some examples, a coating, such as a hydroxyapatite coating, is disposed on the surface of the porous PAEK medical implant after the additive manufacturing process and after annealing. The coating can be disposed by a coating process such as dip coating, immersion coating, or spray coating. The coating is disposed on all surfaces of the porous PAEK medical implant, such as extending through the internal porous structure of the medical implant.

[0129] Example

[0130] Unless otherwise stated, all testing was performed on PEEK articles formed by fused filament fabrication 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 the ASTM F2077 test standard.

[0133] refer to Fig.11A and Fig. 11B , the compressive strength of PEEK cervical spine implants was measured using a static axial compression test. Fig.11A , it was found that the compressive strength of the PEEK cervical spine implant exceeded 25 kN, which means that the PEEK cervical spine implant partially failed after applying a force of 25 kN. Fig. 11B is a photograph of a PEEK cervical spine implant after a 25 kN compressive force was applied and shows that the implant remained substantially intact and only partially failed.

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

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

[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, which is approximately the 75th percentile of FDA published data.

[0137] Further mechanical testing of porous PEEK cervical interbody fusion cages without radiographic markers was performed to confirm that the PEEK structure, rather than the radiographic markers, was responsible for the observed mechanical properties.

[0138] Dynamic axial compression testing of PEEK cervical interbody implants without radiographic markers. Fig. 12A Photo showing the implant before testing, Fig. 12B A photograph of the implant after 5,00,000 cycles is shown. As shown in the photograph, the dynamic axial compression test caused essentially no mechanical damage. Table 1 shows the height measurements for each of the two samples, confirming that the implant remained structurally intact:

[0139]

[0140] Table 1. Dynamic Axial Compression Test Height Measurements of PEEK Implants without Radiographic Markers after 5,000,000 Cycles

[0141] The PEEK cervical interbody implants without radiographic markers were also subjected to drop weight clinical impact testing. The samples were tested according to the test parameters listed in Table 2.

[0142] sample Impact energy(J) Speed ​​(m / s) Drop 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 weight 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. Drop hammer clinical impact test results

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

[0148] About human bone marrow stromal cell (hBMSC) osteogenesis, characterized the osteogenic potential of PEEK cervical vertebra implants with various microstructures and surface chemistry. The assay determines whether hBMSC is transformed into osteoblasts, i.e. bone forming cells, after being exposed to a specific surface. This transformation is mainly demonstrated by surface cell markers and the resulting gene expression and protein production. It is believed that the material proving this cell transformation has osteogenic potential. As shown in this embodiment, porous PEEK cervical vertebra implants are shown to have osteogenic potential in this assay.

[0149] Fig.13 The test method flow is shown. On the 0th day of the test, hBMSCs were plated on four substrates: tissue culture polystyrene (TCPS) as a control, porous PEEK cervical vertebra implants (PP) manufactured as described above, porous PEEK cervical vertebra implants (PP-HA) with HA coatings, and solid PEEK blocks (SP). The cells were cultured for fourteen days, after which the cultures were exposed to 24 hours of fresh conditioned culture medium. Cell layer lysates were extracted and measured, and the results included osteocalcin, osteopontin, osteoprotegerin, vascular endothelial growth factor (VEGF) and DNA. The measurements of interleukins, BMP-2, BMP-4, BgLAP, RUNX-2 and SP7 including IL-4, IL-10 and IL6 were also performed.

[0150] Fig.14 Results of hBMSC assays are shown, demonstrating the effects of various surface chemistries and microarchitectures on the osteogenic potential of the constructs as indicated by protein production, including concentrations of DNA, osteocalcin, osteopontin, osteoprotegerin, and vascular endothelial growth factor 165. Fig.15 Interleukin production is shown, again demonstrating the influence of surface chemistry and microstructure on the osteogenic potential of the construct. Fig.15 The top and bottom rows represent two different experimental runs, generally showing consistent results. Fig.16 The hBMSC cultures described above were also assayed to characterize gene expression to further demonstrate the osteogenic potential of the constructs.

[0151] A summary of the results and their significance is provided in Table 4 .

[0152]

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

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

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

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

[0157] refer to Fig.17 In another experiment, a macrophage polarization assay was performed to characterize the immunomodulatory potential of the implant. The macrophage polarization assay verifies the response of naive macrophages (e.g., present during inflammation, injury, or early episodes of surgery) to a specific surface. M1 macrophages clear debris and elicit pro-inflammatory cytokines, while macrophages that transition to the M2 phenotype are pro-regenerative macrophages. M1 phenotype macrophages exhibit specific gene expression that leads to fibrous tissue formation. M2 phenotype macrophages release different proteins that lead to pro-regenerative, anti-inflammatory regeneration, and thus bone formation.

[0158] Indicators of pro-inflammatory M1 macrophages resulted in expression of iNOS, TNF-α, IL-6, and IL-1β. Indicators of pro-regenerative (anti-inflammatory) M2 macrophages resulted in expression of Arg1, Mrc1, TGF-β1, IL-4, and VEGF. As shown below, consistent with this behavior, the PP and PP-HA surfaces expressed up- and down-regulation of genes and proteins to confirm the shift to an M2 phenotype, indicating immunomodulatory behavior of the PP and PP-HA structures.

[0159] At the beginning of the method, macrophages were harvested and expanded for seven days, during which the culture medium was replaced with a culture medium containing macrophage colony stimulating factor (MCSF). After seven days of macrophage expansion, macrophages were plated and dropwise plated onto a surface containing MCSF. Macrophage experiments were subsequently performed. Specifically, after two days of plating, the culture medium was replaced with fresh culture medium and five test groups were determined: porous PEEK (PP), porous PEEK with HA coating (PP-HA), solid PEEK (SP) and two control groups treated with M1 and M2, respectively. MCSF was not provided to any test group.

[0160] Assay results indicative of a proinflammatory response (e.g., M1 expression) are as follows Fig.18 As shown, and it is shown that porous PEEK inhibits the M1 inflammatory phase, especially relative to solid PEEK. The results of the assays representing tissue repair responses (e.g., M2 expression) are shown. Fig.19 As shown, and it is shown that porous PEEK promotes M2 expression (pro-regeneration and leads to bone formation). Further assays were performed seven days after plating. These results are shown in Figures 219 and 2120 and are generally consistent with Fig.18 and Fig.19 The results of the two days were consistent: porous PEEK inhibited the inflammatory phase and promoted M2 expression.

[0161] These results demonstrate that up- and down-regulation of genes and proteins by PP and PP-HA samples results in polarization of macrophages to a pro-regenerative M2 phenotype and expected gene and protein expression / production. These results also demonstrate suppression and down-regulation of pro-inflammatory genes and proteins of the M1 phenotype.

[0162] These results are generally consistent with the hBMSC assay discussed above: PEEK samples showed markers indicative of bone growth to a greater extent than control samples. In summary, these validated cell assays confirm that porous PEEK fabricated according to the above-described fused filament fabrication process and porous PEEK with HA coatings demonstrate both osteogenic potential and immunomodulatory (immuno-osteogenic), which is generally an unusual behavior for PEEK surfaces.

[0163] Notably, the above assays favor materials known to be hydrophilic and physiological (e.g., Ca / P chemistry) with submicron surface morphology, needle-like morphology, and submicron pore size. The porous PEEK implants described herein possess these characteristics. Specifically, these results demonstrate that porous PEEK implants even without HA coatings possess sufficient properties (e.g., properties imparted by the fused filament fabrication process) to provide positive results in these assays.

[0164] The above osteogenic experiments were performed as follows. Human female MSCs (23-year-old Caucasian) were cultured to confluence in MSC growth medium (GM) before plating onto the test surface. The test plates from each group were plated with 0.5 mL per well, 10,000 cells / cm 2 The density of (20,000 cells / mL / well) was placed in a 24-well plate. After 24 hours of plating, the GM was replaced, and the subsequent GM was replaced every 48 hours until 14 days. At the beginning of the 14th day, the culture medium was replaced with fresh GM and the cells were incubated for 24 hours before harvesting. During harvesting, the culture medium was collected and aliquoted into 1.5mL Eppendorf centrifuge tubes. The wells with MSCs were rinsed twice with 1mL of phosphate buffered saline (PBS), placed in 0.5mL of 0.05% Triton-X100, and frozen at -80°C for bioassay.

[0165] In order to analyze DNA content, by 40V ultrasonic treatment 10 seconds / well to crack the cell layer and determine the total DNA content by fluorescence.According to the manufacturer's scheme, the protein and cytokine production level in the conditioned medium is quantitatively measured using enzyme-linked immunosorbent assay.The protein analyzed includes 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] The following experimental protocol was followed to characterize the macrophage polarization response to various implants using primary naive bone marrow-derived macrophages.

[0167] Naive macrophages were cultured on TCPS, porous PEEK (PP), porous PEEK plus hydroxyapatite (PP-HA), and solid PEEK (SP) for 1 and 3 days in RPMI basal medium supplemented with 10% fetal bovine serum (FBS), 1% penicillin / streptomycin Pen / Strep, and 30ng / mL macrophage colony stimulating factor (M-CSF). These cultures were compared with the phenotype of M1 and M2 induced macrophages. M1 was induced by supplementing interferon-γ (IFN-γ) and lipopolysaccharide (LPS) in the growth medium, and M2 was induced using IL-4 / IL-13. M1 and M2 induced macrophages were compared with naive macrophages cultured on the 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. Gene expression of inducible nitric oxide synthase (iNOS), a marker of the M1 phenotype, and arginine-1 (Arg1), a marker of the M2 phenotype, was determined.

[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 flushed out from the femurs of mice 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 plated at a density of 500,000 cells / mL in 10mL RPMI 1640 culture medium supplemented with 10% FBS, 50U / mL penicillin-50μg / mL streptomycin and 30ng / mL macrophage colony stimulating factor on 75cm 2 Cells were cultured at 37°C, 5% CO2 and 100% humidity. Seven days after plating to generate a homogenous population of naive macrophages, macrophages were passaged using Accutase and plated at 20,000 cells / cm 2 It is seeded on a specified surface at a density of .

[0169] For surface plating, PP, PP-HA and SP samples were washed and gamma irradiated. Naive macrophages were plated on the surface in RPMI1640 medium with 30 ng / mL M-CSF and the phenotype of macrophages induced by M1 and M2 plated on TCPS was compared. The M1 phenotype was induced by supplementing the growth medium with IFN-γ (20 ng / ml) and LPS (100 ng / mL) at the time of plating. M2 was induced using IL-4 / IL-13 (20 ng / ml each) at the time of plating. Macrophages were plated at 10,000 cells / cm 2Cells were plated on the surface of a 24-well plate at a density of (20,000 cells / mL / well). RPMI 1640 containing M-CSF was replaced 24 hours before harvesting.

[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 of PBS and aspirated. 1 mL of 0.05% Triton-X was added and frozen overnight at -20 ° C. According to the manufacturer's protocol, ELISA was used to quantify the secreted inflammatory markers TNFα, IL1β, IL4, IL6, IL10 and IL13 in response to the surface. The immunoassay results were standardized to the dsDNA content in the cell lysate. The culture medium was analyzed by ELISA according to the manufacturing protocol.

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

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

[0173] Various types of PEEK implants including porous PEEK implants, porous PEEK implants with HA coatings and solid PEEK implants were implanted in elderly female sheep (4-5 years old). The implant was 25mm × 6mm outer diameter. Implants were evaluated for bone growth at the bone-implant interface 4 weeks and 12 weeks after surgery. Surface characterization of implants was performed using optical microscope and scanning electron microscope before implantation. The mechanical properties of implants in cortical and cancellous bone implantation sites and cortical bone sites were evaluated over time by radiography. New bone formation was evaluated over time based on conventional PMMA histology in cortical and cancellous sites.

[0174] The implants were placed in the cancellous bone of the distal femur and proximal tibia in a press fit and in the cortical bone of the tibia in a line-to-line fashion. The samples were examined using a standard shear stress push-out test as well as histological and morphological examinations at 4 and 12 weeks after surgery.

[0175] At the appointed time point, each animal is euthanized and inspected and dissected according to SOP-28.Harvest right hind limb and left hind limb, take pictures and carry out radiography.Use Siemens Inveon Micro CT to scan tibia and femur to provide high resolution scanning of bone-implant interface and to assess any osseointegration.Cancellous part is separated and fixed in cold phosphate buffered formalin.Cortical part is separated and sliced ​​on sagittal plane to separate medial and lateral samples for push-out test.

[0176] Process cortex and cancellous samples immediately after separation to carry out PMMA histological analysis.According to SOP-24, sample is placed in 10% buffered formalin and dehydrated in the ethanol of increasing concentration successively, for embedding in polymethylmethacrylate (PMMA).According to SOP-35, Leica SP 1600 slicer is used to slice the embedded cortex and cancellous implant along the long axis of implant.From each embedded implant, cut at least two thin (15-20 micron) sections and dye with methylene blue and basic fuchsin, cause bone to be dyed pink and fibrous tissue to be dyed blue or purple.

[0177] Fig.22A and Fig. 22B Included are images showing histology 4 weeks after implantation of porous PEEK implants with HA coating. Fig. 22B , the lighter translucent band in the image of the implant indicates that the PEEK is amorphous, while the opaque areas are crystalline. Fig.23 Included are images showing histology 12 weeks post-implantation. These images demonstrate bone infiltration and osseointegration throughout the implant, demonstrating the effectiveness of the implant in promoting osteoconduction, osseointegration, and osteogenesis.

[0178] Fig.24 Included are additional images showing histology 12 weeks after implantation of a porous PEEK implant with a HA coating. These images show the stratification of the PEEK in the implant itself: the lighter translucent bands are amorphous areas, while the opaque areas are crystalline. Cortical bone, which is usually stained purple, has grown through the implant without obvious fibrous tissue growth. There are blood vessels, such as those formed by epithelial cells and that allow the bone to be supplied with bone marrow, blood, etc. Osteoblasts and osteocytes are also present, indicating healthy new bone growth.

[0179] Fig.25A and Fig.25B Includes porous PEEK implants showing HA coating ( Fig.25A ) and porous PEEK implants without HA coating ( Fig.25B ) Histological images 12 weeks after implantation in different animals. These images show new bone growth throughout the porous structure of both implants.

[0180] Fig.26 This is a 12-week histological image of a porous PEEK implant without HA coating implanted in the metaphyseal region. This image shows cancellous bone growth throughout the porous structure of the implant.

[0181] Figure 27-Figure 28 Figure 12 histology images of porous PAEK implants from sheep showing the quality of bone formation in the implants. Fig. 27 Includes transmitted light images and Fig.28 Includes stereomicroscope images. These images demonstrate the formation of bone structures in the implant, such as blood vessels, osteocytes, annular bone formation, etc.

[0182] Fig.29 1 is a micro-computed tomography (micro-CT) image taken 12 weeks after implanting a porous PEEK implant with a HA coating. These images demonstrate bone growth around and throughout the implant. For example, the outside and inside of the bone where a bore has been created to insert the implant show healing bone growth. Specifically, white areas such as area 60 are original 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 is comprised of a continuous length of PAEK, wherein the continuous length of PAEK in at least one layer comprises: an interior, and an exterior surface comprising a crystalline region, wherein the exterior surface has a higher degree of crystallinity than 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 outside the plane defined by the layer, or both. The multilayer PAEK defines a network of interconnected pores.

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

[0185] In embodiment 3, which may be combined with embodiment 2, the rows have a serpentine, curved or zigzag configuration.

[0186] In embodiment 4 which may be combined with any of embodiments 2 or 3, the rows in each layer are rotated relative to the rows in adjacent layers.

[0187] In embodiment 5 which may be combined with embodiment 4, the rows in each layer are rotated 20-60° relative to the rows in the adjacent layer.

[0188] In embodiment 6, which may be combined with embodiment 5, the rows in each layer are rotated 36° relative to the rows in the adjacent layer.

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

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

[0191] In embodiment 9 which may be combined with any of the preceding embodiments, each layer defines a plane, and wherein a portion of the continuous length of PAEK in each layer extends outside of the plane defined by the layer.

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

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

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

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

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

[0197] In embodiment 15, which may be combined with embodiment 14, the layered surface microstructure forms beads on the outer surface of the continuous length of PAEK.

[0198] In embodiment 16 which may be combined with embodiment 15, the beads have a characteristic size of 4-6 μm.

[0199] In embodiment 17 which may be combined with any of the preceding embodiments, the continuous lengths of PAEK in a first set of layers of the multilayer have a different crystallinity than the continuous lengths of PAEK in a second set of layers of the multilayer.

[0200] In embodiment 18 which may be combined with any of the preceding embodiments, the multiple layers of PAEK define a trabecular structure.

[0201] In embodiment 19 which may be combined with any of the preceding embodiments, the multiple layers of PAEK form a tri-periodic minimal surface (TPMS) structure defining a network of interconnected pores.

[0202] In embodiment 20 which may be combined with embodiment 19, multiple layers of PAEK form a TPMS diamond structure.

[0203] In embodiment 21 which may be combined with any of the preceding embodiments, the continuous length of PAEK has a surface roughness between 0.5 μm and 3.0 μm.

[0204] In embodiment 22 which may 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 may be combined with any of the preceding embodiments, the article has a Young's modulus of elasticity between 0.3 GPa and 4.0 GPa.

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

[0207] In embodiment 25, which may be combined with any of the preceding embodiments, the article has a compressive strength of at least 20 kN.

[0208] In embodiment 26, which may be combined with embodiment 25, the article has a compressive strength between 20 kN and 150 kN.

[0209] In embodiment 27, which may be combined with embodiment 26, the article has a compressive strength between 20 kN and 100 kN.

[0210] In embodiment 28, which may be combined with embodiment 27, the article has a compressive strength between 20 kN and 30 kN.

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

[0212] In embodiment 30, which may be combined with any of the preceding embodiments, the article has a stiffness between 0.8 GPa and 1.5 GPa.

[0213] In embodiment 31 , which may be combined with any of the preceding embodiments, the article comprises a coating comprising hydroxyapatite disposed on an outer surface of the continuous length of PAEK.

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

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

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

[0217] In embodiment 35, which may be combined with any of the preceding embodiments, the continuous length of PAEK has a crystallinity between 20 vol% and 60 vol%.

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

[0219] In embodiment 37, which may be combined with any of the preceding embodiments, the article has a porosity of 40-80%.

[0220] In embodiment 38 which may be combined with any of the preceding embodiments, the size of the pores is 100 μm to 1 mm.

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

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

[0223] In embodiment 41 which may be combined with any of the preceding embodiments, PAEK includes polyetheretherketone (PEEK).

[0224] In embodiment 42, which may be combined with any of the preceding 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 may be combined with embodiment 42, a continuous length of PAEK extends between the first region and the second region.

[0226] In embodiment 44, which may be combined with any of the preceding embodiments, the continuous length of PAEK is deposited by additive manufacturing.

[0227] In embodiment 45, which may be combined with embodiment 44, a continuous length of PAEK is deposited by fuse fabrication.

[0228] In embodiment 46, which may be combined with any of the preceding embodiments, the article comprises a medical implant.

[0229] In embodiment 47 which may be combined with embodiment 46, the medical implant is osteoconductive.

[0230] In embodiment 48 which may be combined with any of embodiments 46 to 47, the medical implant is osseointegrated.

[0231] In embodiment 49 which may be combined with any of embodiments 46 to 48, the medical implant is osteogenic.

[0232] In embodiment 51, the medical implant comprises multiple layers of PAEK deposited by fuse fabrication, wherein each layer is comprised 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 comprises: an interior, and an exterior surface comprising a crystalline region, wherein the crystallinity of the exterior surface is higher than the crystallinity 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 interconnected pores, such that the porosity of the medical implant is 50-70%, and wherein the medical implant is osteoconductive.

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

[0234] In embodiment 53 which may be combined with any of embodiments 51 to 52, the medical implant comprises 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 may be combined with any of embodiments 51 to 53, the medical implant comprises a joint implant.

[0236] In embodiment 55, the medical implant is produced by a process comprising:

[0237] extruding a filament of PAEK from a nozzle of an additive manufacturing tool to deposit each layer of a plurality of layers of PAEK, wherein each layer is comprised of a continuous length of PAEK; and

[0238] annealing the deposited multilayer to induce crystallization of regions of an outer surface of the continuous length of PAEK, wherein the outer surface of the continuous length of PAEK has a higher degree of crystallinity than the interior,

[0239] The multiple layers of PAEK define a network of interconnected pores.

[0240] In embodiment 56, which may be combined with embodiment 55, the process includes extruding filaments of PAEK, and the extruding filaments of PAEK includes forming aligned rows of continuous lengths of PAEK in each layer.

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

[0242] In embodiment 58, which may 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 the continuous length of PAEK extends outside of the plane defined by the layer.

[0243] In embodiment 59, which may be combined with any of embodiments 55 to 58, the process includes extruding filaments of PAEK such that a continuous length of PAEK in each layer intersects a continuous length of PAEK in an adjacent layer at a node.

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

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

[0246] In embodiment 62, which may be combined with any of embodiments 55 to 61, the process includes extruding filaments of PAEK such that the multiple layers form a tri-periodic minimal surface (TPMS) structure defining a network of interconnected pores.

[0247] In embodiment 63 which can be combined with embodiment 62, multiple layers form a TPMS diamond structure.

[0248] In embodiment 64 which may 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 may be combined with embodiment 64, the process includes rotating the additive manufacturing tool 20-60° after depositing each layer.

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

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

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

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

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

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

[0256] In embodiment 72 which may be combined with embodiment 71, it includes extruding the filaments of PAEK at an extrusion ratio of 0.5-2.0.

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

[0258] In embodiment 74 which may 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 the PAEK.

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

[0260] In embodiment 76, which may be combined with any of embodiments 55 to 75, the process includes disposing a coating comprising hydroxyapatite onto an outer surface of the continuous length of PAEK.

[0261] In embodiment 77 which may be combined with embodiment 76, providing the coating includes providing the coating by dipping, immersion coating or spraying.

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

[0263] In embodiment 79, which may be combined with any of embodiments 55 to 77, the process includes extruding filaments of PAEK using a fused filament fabrication process.

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

[0265] In embodiment 81, which may be combined with any of embodiments 55 to 80, the process includes extruding filaments 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 multiple layers.

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

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

Claims

1. A product comprising: A multilayer polyaryletherketone (PAEK), wherein each layer is composed of a continuous length of PAEK, wherein the continuous length of PAEK in at least one layer comprises: Internally, and an outer surface comprising a crystalline region, wherein the outer surface has a higher degree of crystallinity than the inner portion; wherein the cross-sectional area of ​​the continuous length of PAEK is non-uniform within each layer, and The multiple layers of PAEK define a network of interconnected pores.

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

4. The article of any one of the preceding claims, wherein the continuous length of PAEK extends between adjacent layers.

5. The article of any one of the preceding claims, wherein each layer defines a plane, and wherein a portion of the continuous length of PAEK in each layer extends out of the plane defined by that layer.

6. The article of any preceding claim, wherein the continuous length of PAEK in each layer intersects the continuous length of PAEK in an adjacent layer at a node, and wherein the continuous length of PAEK extending between adjacent nodes is non-linear.

7. The article of any one of the preceding claims, wherein the outer surface of the continuous length of PAEK comprises crystalline domains separated by amorphous regions.

8. The article of any one of the preceding claims, wherein the outer surface of the continuous length of PAEK comprises a lamellar surface microstructure, wherein the lamellar surface microstructure has a characteristic size of 4-6 nm.

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

10. The article of any one of the preceding claims, wherein the continuous length of PAEK in a first set of layers of the multilayer has a different crystallinity than the continuous length of PAEK in a second set of layers of the multilayer.

11. The article of any one of the preceding claims, wherein the multiple layers of PAEK define a beam structure.

12. The article of any preceding claim, wherein the multi-layer PAEK forms a three-periodic minimal surface TPMS structure defining a network of interconnected pores.

13. The article of any preceding claim, wherein the continuous length of PAEK has a surface roughness between 0.5 μm and 3.0 μm.

14. The article according to any one of the preceding claims, wherein the article has a Young's modulus of elasticity between 0.3 GPa and 4.0 GPa.

15. The article of any preceding claim, wherein the article has a compressive strength of at least 20 kN.

16. The article according to any one of the preceding claims, wherein the fatigue strength of the article is between 1200N and 1800N measured at 5 Hz over 5 million cycles.

17. The article of any one of the preceding claims, wherein the continuous length of PAEK has a crystallinity between 20 and 60 volume percent.

18. The article of any preceding claim, wherein the article has a porosity of 40-80%.

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

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

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

22. An article comprising: A multilayer polyaryletherketone (PAEK), wherein each layer is composed of a continuous length of PAEK, wherein the continuous length of PAEK in at least one layer comprises: Internally, and an outer surface comprising a crystalline region, wherein the outer surface has a higher degree of crystallinity than the inner portion; wherein each layer defines a plane, and wherein a portion of the continuous length of PAEK in each layer extends outside the plane defined by the layer, and The multiple layers of PAEK define a network of interconnected pores.

23. The article of claim 22, wherein the continuous lengths of PAEK in each layer are arranged in aligned rows, and wherein the rows in each layer are rotated relative to the rows in adjacent layers.

24. The article of claim 22 or 23, wherein the continuous length of PAEK extends between adjacent layers.

25. The article of any one of claims 22 to 24, wherein the continuous length of PAEK in each layer intersects the continuous length of PAEK in an adjacent layer at a node, and wherein the continuous length of PAEK extending between adjacent nodes is non-linear.

26. The article of any one of claims 22 to 25, wherein the outer surface of the continuous length of PAEK comprises crystalline domains separated by amorphous regions.

27. The article of any one of claims 22 to 26, wherein an outer surface of the continuous length of PAEK comprises a layered surface microstructure.

28. The article of any one of claims 22 to 27, wherein the continuous length of PAEK in a first set of layers of the multilayer has a different crystallinity than the continuous length of PAEK in a second set of layers of the multilayer.

29. A medical implant comprising: Multiple layers of PAEK deposited by fuse fabrication, wherein each layer is comprised 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 comprises: Internally, and An outer surface comprising a crystalline region, wherein the crystallinity of the outer surface is higher than the crystallinity of the inner portion, 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 interconnected pores, such that the porosity of the medical implant is 50-70%, and Wherein the medical implant is osteoconductive.

30. A medical implant produced by a process comprising: extruding a filament of PAEK from a nozzle of an additive manufacturing tool to deposit each layer of a plurality of layers of PAEK, wherein each layer is comprised of a continuous length of PAEK; and annealing the deposited multilayer to induce crystallization of regions of an outer surface of the continuous length of PAEK, wherein the outer surface of the continuous length of PAEK has a higher degree of crystallinity than the interior, The multiple layers of PAEK define a network of interconnected pores.

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