Additively manufactured porous polymer medical implants

Abstract

The article includes multiple layers of polyaryletherketone (PAEK), each layer comprised of a continuous length of PAEK, the continuous length of PAEK in at least one layer including an interior and an exterior surface including crystalline regions, the exterior surface having a higher crystallinity than the interior. The cross-sectional area of ​​the continuous length of PAEK is non-uniform within each layer. Each layer defines a plane, and a portion of the continuous length of PAEK in each layer extends outwardly from the plane defined by that layer. The multiple layers of PAEK define a network of interconnected pores.

Description

[Technical Field]

[0001] Priority claims This application claims priority to U.S. Patent Application No. 63 / 429,746, filed December 2, 2022, and U.S. Patent Application No. 63 / 329,209, filed April 8, 2022, the contents of both applications being incorporated herein by reference in their entireties. [Background technology]

[0002] Medical implants are devices placed within the body to replace or support biological structures such as bone. Summary of the Invention [Means for solving the problem]

[0003] In a first aspect, an article includes multiple layers of polyaryletherketone (PAEK), each layer being composed of a continuous length of PAEK, and the continuous length of PAEK in at least one layer includes an interior and an exterior surface comprising crystalline regions, the exterior surface having a higher 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 that layer, or both. The multiple layers of PAEK define a network of interconnected pores.

[0004] Embodiments may include one or any combination of two or more of the following features.

[0005] The continuous lengths of PAEK in each layer are aligned. 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 adjacent layers. In some cases, the rows in each layer are rotated 20 to 60 degrees relative to the rows in adjacent layers. In some cases, the rows in each layer are rotated 36 degrees relative to the rows in adjacent layers.

[0006] The cross-sectional area of ​​the continuous length of PAEK is non-uniform within each layer.

[0007] A continuous length of PAEK extends between adjacent layers.

[0008] Each layer defines a plane, and a portion of the continuous length of PAEK in each layer extends outwardly from the plane defined by that layer.

[0009] The continuous length of PAEK in each layer intersects the continuous length of PAEK in the adjacent layer at a node, and in some cases the continuous length of PAEK extending between adjacent nodes is non-linear.

[0010] The outer surface of a continuous length of PAAK comprises crystalline domains separated by amorphous regions.

[0011] 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 spheroids on the outer surface of the continuous length of PAEK. In some cases, the spheroids have a characteristic dimension of 4-6 μm.

[0012] The continuous lengths of PAEK in the layers of the first set of layers have a different crystallinity than the continuous lengths of PAEK in the layers of the second set of layers.

[0013] The multiple layers of PAEK define a trabecular structure.

[0014] Multiple layers of PAEK form a triple periodic minimal surface (TPMS) structure that defines a network of interconnected pores. In some cases, multiple layers of PAEK form a TPMS diamond structure.

[0015] The surface roughness of the continuous length of PAEK is 0.5 μm to 3.0 μm, for example 1 μm to 1.5 μm.

[0016] The Young's modulus of the article is between 0.3 GPa and 4.0 GPa, for example between 0.8 GPa and 1.5 GPa.

[0017] The compressive strength of the article is at least 20 kN, for example, from 20 kN to 150 kN, from 20 kN to 100 kN, or from 20 kN to 30 kN.

[0018] The fatigue strength of the article measured at 5Hz over 5M cycles is between 1200N and 1800N.

[0019] The stiffness of the article is 0.8 GPa to 1.5 GPa.

[0020] The article includes a coating comprising hydroxyapatite applied to the outer surface of the continuous length of PAEK. In some cases, the coating has a thickness of from 1 nm to 80 nm, such as from 1 nm to 50 nm, or from 1 nm to 20 nm.

[0021] A continuous length of PAEK has a crystallinity of 20% to 60% by volume, for example 30% to 50% by volume.

[0022] The article has a porosity of 40 to 80%.

[0023] The size of the pores is 100 μm to 1 mm, for example, 100 μm to 700 μm.

[0024] The average size of the pores is 220 to 280 μm.

[0025] PAEK includes polyetheretherketone (PEEK).

[0026] The plurality of layers of PAEK define a first region having a first porosity and a second region having a second porosity different from the first porosity, both the first region and the second region spanning at least a portion of the plurality of layers. In some cases, a continuous length of PAEK extends between the first region and the second region.

[0027] Continuous lengths of PAEK are laid up by additive manufacturing such as fused strand manufacturing.

[0028] The article includes a medical implant. Optionally, the medical implant is osteoconductive. Optionally, the medical implant is osteointegrative. Optionally, the medical implant is osteogenic.

[0029] In a second aspect combinable with the first aspect, a medical implant includes multiple layers of PAEK laminated by fused strand fabrication, each layer being composed of a continuous length of PAEK arranged in an aligned manner, the continuous length of PAEK extending between adjacent layers, the continuous length of PAEK in at least one layer including an interior and an exterior surface comprising crystalline regions, the crystallinity of the exterior surface being higher than the crystallinity of the interior, the cross-sectional area of ​​the continuous lengths of PAEK being non-uniform within each row, the rows in each layer being rotated relative to the rows in each adjacent layer, forming a TPMS diamond structure defining a network of interconnected pores such that the porosity of the medical implant is 50-70%, and the medical implant is osteoconductive.

[0030] Embodiments may include one or any combination of two or more of the following features.

[0031] The medical implants include cervical implants.

[0032] The medical implants include a posterior lumbar interbody fusion implant, a transforaminal interbody fusion implant, an anterior lumbar interbody fusion implant, or a direct lateral interbody fusion implant.

[0033] Medical implants include joint implants.

[0034] In a third aspect combinable with the first and second aspects, the medical implant is manufactured by a method comprising: extruding a filament of PAEK from a nozzle of an additive manufacturing tool to deposit each of a plurality of PAEK layers, each layer comprising a continuous length of PAEK; and annealing the deposited plurality of layers to induce crystallization of an outer surface region of the continuous length of PAEK, wherein the crystallinity of the outer surface is higher than the crystallinity of an interior of the continuous length of PAEK, and wherein the plurality of PAEK layers define a network of interconnected pores.

[0035] Embodiments may include one or any combination of two or more of the following features.

[0036] The process of extruding filaments of PAEK involves forming continuous lengths of aligned PAEK in each layer.

[0037] The method includes continuously extruding a filament of PAEK to form adjacent layers, with a continuous length of PAEK extending between adjacent layers.

[0038] The method includes extruding a filament of PAEK such that each layer defines a plane and a portion of the continuous length of PAEK extends outside the plane defined by that layer.

[0039] The method includes extruding filaments of PAEK such that a continuous length of PAEK in each layer intersects with a continuous length of PAEK in an adjacent layer at a node, and in some cases, the continuous length of PAEK extending between adjacent nodes is non-linear.

[0040] The method includes extruding a filament of PAEK such that a continuous length of PAEK has a non-uniform cross-sectional area within each layer.

[0041] The method includes extruding a filament of PAEK such that multiple layers form a triple periodic minimal surface (TPMS) structure that defines a network of interconnected pores. In some cases, the multiple layers form a TPMS diamond structure.

[0042] The method includes rotating the additive manufacturing tool after depositing each layer of PAEK. In some cases, the method includes rotating the additive manufacturing tool by 20-60 degrees after depositing each layer.

[0043] The method includes heating a nozzle of the production tool to a temperature of 325-475°C, such as a temperature of 400-450°C.

[0044] The process of extruding a filament of PAEK involves laying up a first layer on a heated platform.

[0045] The method includes extruding a filament of PAEK at an extrusion rate of 10-15 mm / s.

[0046] The method includes moving the nozzle relative to the deposited layers at a feed rate of 5 to 15 mm / s.

[0047] The method includes extruding a PAEK filament at an extrusion ratio of 0.5 to 4.0, where the extrusion ratio is the ratio of the extrusion flow rate of the PAEK to the speed of movement of the nozzle relative to the laminate layer. In some cases, the PAEK filament is extruded at an extrusion ratio of 0.5 to 2.0, e.g., an extrusion ratio of 0.6 to 1.0.

[0048] The method includes annealing the stacked layers at a temperature below the glass transition temperature of the PAEK. Optionally, annealing the stacked layers includes forming a lamellar surface microstructure on the outer surface of the continuous length of PAEK.

[0049] The method includes applying a coating comprising hydroxyapatite to an outer surface of the continuous length of PAEK. Optionally, applying the coating includes applying the coating by dip coating, immersion coating, or spray coating.

[0050] The method involves extruding filaments of PAEK using a melt strand lamination process.

[0051] The method includes extruding a filament of PAEK using fused filament fabrication.

[0052] The method involves extruding a filament of PAEK using fused deposition modeling.

[0053] The method 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, both the first region and the second region spanning at least a portion of the plurality of layers. In some cases, a continuous length of PAEK extends between the first region and the second region.

[0054] The approaches described herein may have one or more of the following advantages: The porous PAEK medical implants described herein have mechanical properties, such as strength and modulus, that are comparable to those of physiological bone. Furthermore, the porous PAEK medical implants described herein are bioactive and exhibit osteogenic behavior (e.g., osteoconduction, osteointegration, and immunomodulation (osteoinduction)). Porous PAEK medical implants with this combination of mechanical and biological properties promote rapid and sustained bone growth when implanted in a subject.

[0055] The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features and advantages will become apparent from the description and drawings, and from the claims. [Brief explanation of the drawings]

[0056] [Figure 1] 1 is a photograph of a porous PAEK medical implant. [Figure 2A] 1 is a schematic representation of the layers of a porous PAEK medical implant. [Figure 2B] 1 is a schematic representation of the layers of a porous PAEK medical implant. [Figure 3A] 1 is an optical image of a porous PAEK medical implant. [Figure 3B] 1 is an optical image of a porous PAEK medical implant. [Figure 4A] 1 is a scanning electron microscope (SEM) image of a porous PAEK medical implant. [Figure 4B] 1 is a scanning electron microscope (SEM) image of a porous PAEK medical implant. [Figure 5A] 1 is an SEM image of a porous PAEK medical implant. [Figure 5B] 1 is an SEM image of a porous PAEK medical implant. [Figure 6A] 1 is an SEM image of a porous PAEK medical implant. [Figure 6B] 1 is an SEM image of a porous PAEK medical implant. [Figure 7] 1 is a schematic representation of a porous PAEK medical implant. [Figure 8A] 1 is a photograph of a porous PAEK medical implant. [Figure 8B] 1 is a photograph of a porous PAEK medical implant. [Figure 8C] 1 is a photograph of a porous PAEK medical implant. [Figure 8D] 1 is a photograph of a porous PAEK medical implant. [Figure 9A] 1 is a photograph of a porous PAEK medical implant. [Figure 9B] 1 is a photograph of a porous PAEK medical implant. [Figure 10] 1 is a schematic diagram of the components of an additive manufacturing system. [Figure 11A]The results of the compression test. [Figure 11B] The results of the compression test. [Figure 11C] The results of the compression test. [Figure 12A] These are the results of mechanical testing. [Figure 12B] These are the results of mechanical testing. [Figure 13] 1 is a test process flow. [Figure 14] 1 is a plot of the results of a human bone marrow stromal cell (hBMSC) assay. [Figure 15] 1 is a plot of the results of a human bone marrow stromal cell (hBMSC) assay. [Figure 16] 1 is a plot of the results of a human bone marrow stromal cell (hBMSC) assay. [Figure 17] 1 is a test process flow. [Figure 18] 1 is a plot of the results of a macrophage assay. [Figure 19] 1 is a plot of the results of a macrophage assay. [Figure 20] 1 is a plot of the results of a macrophage assay. [Figure 21] 1 is a plot of the results of a macrophage assay. [Figure 22] This is a histological image. [Figure 23] This is a histological image. [Figure 24] This is a histological image. [Figure 25] This is a histological image. [Figure 26] This is a histological image. [Figure 27] This is a histological image. [Figure 28] This is a histological image. [Figure 29] FIG. 1 includes a micro-computed tomography image. DETAILED DESCRIPTION OF THE INVENTION

[0057] This paper describes medical implants formed by additive manufacturing of polyaryletherketone (PAEK), e.g., melt strand deposition of PAEK. The resulting medical implants have a loose lattice structure that defines a network of interconnected pores and mimics the structure of physiological (e.g., trabecular) bone. The implant's PAEK strands are semi-amorphous internally and have crystalline domains on the outer surface, providing a surface roughness that also mimics the physiological environment. The implant's PAEK strands are non-uniform in cross-sectional area and non-linear. For example, the PAEK strands in one layer have a tapering profile that extends to the underlying layer.

[0058] These porous PAEK medical implants have mechanical properties, such as strength and modulus, that are comparable to or exceed those of physiological bone. Furthermore, these porous PAEK medical implants are biologically active, exhibiting osteoconductive, osteointegrative, osteogenic, and immunomodulatory behavior.

[0059] Referring to FIG. 1, a medical implant 100 is a porous structure formed from multiple additively manufactured layers of polyaryletherketone (PAEK) thermoplastic, such as polyetherketone (PEK), polyetheretherketone (PEEK), polyetherketoneketone (PEKK), polyetheretherketoneketone (PEEKK), or polyetherketoneetherketoneketone (PEKEKK). Each layer of PAEK is comprised of one or more continuous lengths of PAEK. The continuous lengths of PAEK are strands of PAEK laminated together by continuous (e.g., uninterrupted) extrusion of the PAEK from an additive manufacturing tool. In the embodiment of FIG. 1, the one or more continuous lengths of PAEK in each layer are arranged in aligned rows 102 (see also FIGS. 2A-2B). However, in some embodiments, the continuous lengths of PAEK are arranged in other configurations. The continuous lengths of PAEK define a network of interconnected pores 104. The medical implant 100 of FIG. 1 is a cervical implant, but other types of bone implants may have a similar structure and composition.

[0060] The medical implant 100 has osteogenic potential. For example, the medical implant is osteoconductive, meaning that bone cells can grow on the surface of the medical implant. The medical implant 100 is also osteointegrative, meaning that a direct structural connection can be formed between the bone and the implant 100, e.g., a connection that cannot be separated without fracture. Furthermore, the medical implant 100 is immunomodulatory (e.g., osteoinductive), meaning that the medical implant can induce bone formation, for example, by recruiting immature cells and stimulating their differentiation into pre-osteoblasts. For example, within a period of about 4-12 weeks after implantation in a living body, nearly all (e.g., greater than 90%, or greater than 95%) of the pore volume of the medical implant 100 is filled with living, natural bone. Without being bound by theory, it is believed that the surface microstructure, pore structure, and composition of the medical implant contribute to the osteogenic (e.g., osteoconductive, osteointegrative, and immunomodulatory / osteoinductive) behavior of the medical implant 100, as described in more detail below.

[0061] Osteoconduction can be characterized in a variety of ways, including histological bone attachment and histological bone quality, physiological bone quality, biomechanical bone quality, bone-implant interface quality, and bone persistence (e.g., longevity). Osteoinduction (e.g., immunomodulation) can be characterized by macrophage polarization arrays, which exhibit regenerative behavior, for example, with muscle pouch implantation. Osteogenesis can be characterized by cell differentiation and gene expression.

[0062] The porous PAEK medical implants described herein have a substantially periodic lattice structure that defines a network of interconnected pores, as described below. This structure provides the medical implant with high compressive strength, modulus, and toughness. The pore interconnectivity and pore size distribution contribute to the osteogenic behavior of the medical implant.

[0063] The surface microstructure of the porous PAEK medical implants described herein contributes to their physiological behavior. For example, the surface crystallinity and surface roughness achieved by the fused strand deposition modeling process strengthen the PAEK, render the surface hydrophilic, mimic physiological biomechanics, and promote bone formation. The surface microstructure, such as the surface nanotexture crystallinity, also mimics physiological bone and contributes to osteogenic behavior (e.g., osteoconduction, osteointegration, and immunomodulation (e.g., osteoinduction)).

[0064] 2A is a schematic diagram of a single layer 200 of a porous PAEK medical implant. Layer 200 is comprised of two continuous lengths 202, 204 of PAEK arranged in aligned rows 206, with each continuous length 202, 204 of PAEK extending between adjacent rows. In some embodiments, each layer of the medical implant is comprised of a single continuous length of PEEK, and in some embodiments, each layer of the medical implant includes multiple continuous lengths of PEEK.

[0065] The rows 206 are spaced apart so that the layer 200 is loosely packed with material, e.g., less than 50%, e.g., less than 30% or less than 25% of the total area of ​​the layer is occupied by PAEK material. For example, the PAEK material in each row is spaced apart from the width w r is 75 μm to 400 μm, and adjacent columns have a width w g are separated by gaps of 50 μm to 500 μm. While the rows 202 of layer 200 in FIG. 2A have a serpentine configuration, in some embodiments the rows have other configurations, such as zigzag, curved, sinusoidal, or linear configurations. In some embodiments, one or more continuous lengths of PAEK in layer 200 are randomly arranged.

[0066] Porous PAEK medical implants include multiple layers stacked on top of each other. Figure 2B shows layer 200 of Figure 2A with a second layer 210 disposed on top of layer 200. Each layer 200, 210 is comprised of one or more continuous lengths of PAEK arranged in an aligned manner, for example, as described with respect to Figure 2A. In some embodiments, a continuous length of PAEK extends between adjacent layers 200, 210, thereby connecting the two layers. Subsequent layers can be similarly configured such that a continuous length of PAEK extends between at least some adjacent layer pairs within the medical implant.

[0067] The orientation of the rows in each layer defines the layer's orientation. In a medical implant, the orientation of each layer differs from the orientation of an adjacent layer, e.g., the rows in one layer are rotated relative to the rows in each adjacent layer. The orientations of layers 200 and 210 are indicated by arrows 208 and 218, respectively. Typically, the rows in one layer of a medical implant are rotated by 20° to 60°, e.g., 20° to 40°, or 30° to 40°, e.g., approximately 36°, relative to the rows in an adjacent layer. In the example of FIG. 2B, the rows in layer 200 are rotated by approximately 30° relative to the rows in layer 210.

[0068] The continuous length of PAEK in each layer (e.g., layer 200) contacts the continuous length of PAEK in an adjacent layer (e.g., layer 210) at a node, e.g., node 220. The PAEK in upper layer 210 is supported by the PAEK in lower layer 200 at node 220, while the portion of the continuous length of PAEK extending between adjacent nodes is unsupported by the lower layer. Due to the loose structure and relative rotation between the layers, as well as the time and temperature profile of the manufacturing process described in more detail below, at least a portion of the unsupported portion of the continuous length of PAEK in a given layer sags from a plane defined by that layer toward a plane defined by the lower layer, e.g., defining a nonlinear connection between the nodes. For example, the unsupported portion of PAEK sagging 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., 10% to 30%, or 25% to 50%. As a specific example, if layers 200, 210 each have a height of about 200 μm, then 75 μm to 100 μm of the unsupported PAEK of upper layer 210 will extend into the plane of the lower layer.

[0069] The time and temperature profile of the manufacturing process also causes the cross-sectional diameter or cross-sectional area of ​​the continuous length of PAEK to be non-uniform 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 the nodes. By way of example, the cross-sectional area of ​​the narrowest portion of the tapered PAEK length (e.g., near the center between the nodes) may be 10% to 50%, e.g., 20% to 40%, 10% to 25%, or 25% to 50% smaller than the cross-sectional area of ​​the widest portion (e.g., at or near the node).

[0070] In some embodiments, one or more of the continuous lengths of PAEK in a medical implant extend between adjacent nodes, e.g., the extrusion of the PAEK is interrupted at each node. In some embodiments, one or more of the continuous lengths of PAEK extend across multiple nodes, e.g., some or all of the nodes in each row of a given layer. In some embodiments, one or more of the continuous lengths of PAEK extend across multiple rows (e.g., as shown in FIG. 2A). The continuous lengths of PAEK in a given medical implant may all be the same length or may be different lengths.

[0071] Figures 3A and 3B are photographs of a porous PEEK medical implant, and Figures 4A and 4B are scanning electron microscope images of the porous PEEK medical implant. These images show the loose porous structure of the medical implant, as well as the nonlinear and nonuniform nature of the continuous length of PEEK between adjacent nodes. These images also show the textured surface of the PEEK, which is described in more detail below.

[0072] As shown in Figures 3A-3B and 4A-4B, the continuous lengths or lengths of PAEK comprising the porous PAEK medical implant form a substantially periodic lattice structure that defines a network of interconnected pores 300. A substantially periodic lattice structure is a structure composed of repeating units with slight variations due to, for example, the manufacturing process. In one embodiment, the PAEK layer forms a triply 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. In the embodiment of Figures 3A-3B and 4A-4B, the PAEK layer can form a TPMS diamond lattice structure that mimics the trabecular structure of bone, thereby providing a columnar structure similar to that provided by natural bone. The TPMS lattice structure has three-dimensional symmetry and a high surface area to volume ratio. This structure also has advantages from a biomechanical perspective, such as favorable system energy and stress and strain distribution. The TPMS lattice structure also has advantages from a biological perspective, such as facilitating fluid flow and permeability, mimicking the cellular microenvironment (e.g., by providing adequate oxygen levels), providing high surface area exposure, and promoting osteointegration.

[0073] The porous PAEK medical implant has a porosity of 40% to 80% by volume, e.g., about 40%, about 50%, about 60%, about 70%, or about 80% by volume. The interconnected pores are those accessible from the exterior of the medical implant. The average size (e.g., diameter) of the pores 300 is 50 μm to 1 mm, e.g., 100 μm to 700 μm, 100 μm to 500 μm, 200 μm to 300 μm, or 220 μm to 280 μm. In some cases, the pores are irregularly shaped, e.g., non-spherical. For example, if 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 implants described herein mimic the structure of trabecular bone, providing a large surface area for contact between the bone and the medical implant, thereby promoting bone formation.

[0074] The crystallinity of the PAEK in porous PAEK medical implants varies between the interior and exterior of the material. For example, in at least some locations of a PAEK medical implant, the crystallinity of the outer surface of the continuous length of PAEK is higher than the crystallinity of the inner portion of the continuous length of PAEK. Specific examples include an inner portion of at least some of the continuous lengths of PAEK in a PAEK medical implant with a crystallinity of less than 50% by volume, e.g., 10% to 50%, 20% to 40%, or 25% to 35% by volume. The crystallinity of the inner portion is sufficiently low that, when imaged, the inner portion appears translucent, e.g., exhibiting translucent brown bands. The outer surfaces of these continuous lengths of PAEK contain crystalline domains with amorphous regions interspersed between them. The crystallinity of the outer surface is higher than the inner portion, e.g., 10% to 50% by surface area. The crystallinity of the semi-crystalline outer surface causes the surface to appear opaque, e.g., a light beige color. Without wishing to be bound by theory, it is believed that the processing conditions, such as the time and temperature profile of the manufacturing process, can result in the formation of a continuous length of PAEK having a semi-amorphous interior and an outer surface comprising crystalline regions.

[0075] The crystalline domains at the outer surface of the continuous length of PAEK have a lamellar surface microstructure. For example, the crystalline domains 506 comprise plate-like, generally hexagonal crystals having a characteristic dimension (e.g., thickness) of 4 nm to 10 nm, e.g., 6 to 10 nm, or about 5 nm, and an in-plane dimension (e.g., length or diameter) of 200 nm to 500 nm, e.g., 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, or 500 nm. A plurality of such lamellar crystals aggregate to form each crystalline domain. For example, the crystalline domains can be spheroids with a radial microstructure and dimensions (e.g., diameter) of 4 μm to 10 μm, e.g., 4 μm to 8 μm, or 4 μm to 6 μm.

[0076] 5A and 5B are SEM images of a portion of a continuous length of PEEK in a medical implant, showing the radial microstructure of the spheroids forming crystalline domains with amorphous regions on the outer surface separating the radial arms of the spheroids.

[0077] The outer surface microstructure of the continuous length of PAEK results in a surface roughness (e.g., root mean square (RMS) surface roughness) of 0.5 μm to 3.0 μm, e.g., 1 μm to 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 bone formation.

[0078] In some embodiments, the relative crystallinity of the interior and exterior surfaces of the PAEK in a porous PAEK medical implant varies depending on the location within the porous PAEK medical implant. The PAEK in a layer formed early in an additive manufacturing process (e.g., the bottom layer of a medical implant oriented in an additive manufacturing system, i.e., referred to as the bottom layer) can have a different crystallinity and crystallinity configuration than the PAEK in a subsequent layer (e.g., the top layer of the medical implant, i.e., referred to as the top layer). The difference in crystallinity can be optically visible, for example, in optical microscope images (e.g., obtained in histological imaging) of thin cross sections of a PAEK medical implant. In transmitted light optical images, substantially amorphous regions of the PAEK appear translucent, while highly crystalline regions appear opaque. In some embodiments, there is a gradient of crystallinity within the highly crystalline, opaque regions.

[0079] "The greater amount of thermal cycling experienced by the lower layers compared to the upper layers is believed to contribute to this microstructural difference. Because the lower layers of a medical implant are formed before the upper layers, they experience more thermal cycling than the upper layers. The difference in the amount of thermal cycling experienced by layers at different locations on the medical implant contributes to the difference in the PAEK microstructure."

[0080] The top layer of PAEK is laminated at a temperature close to the glass transition temperature of the PAEK. After lamination, the outer surface of the PAEK cools rapidly, solidifying the arrangement of the unorganized polymer chains. The interior of the PAEK cools more slowly than the outer surface, developing a more organized crystalline structure. A similar cooling process occurs in the bottom layer of PAEK. However, the bottom layer of PAEK undergoes an additional thermal cycle as a new layer is laminated on top of it. At the nodes where the top layer meets the bottom layer, the newly laminated layer remelts the outer surface of the bottom layer. The material previously on the outer surface at the node now becomes the interior of the PAEK at the node, where it cools more slowly and crystallizes. Furthermore, the lamination of the top layer reheats the other outer surfaces of the bottom PAEK layer, promoting the reorganization of the polymer chains on the outer surface and increasing the crystallinity of the outer surface.

[0081] As a result of such differences in thermal cycling, the PAEK in the bottom layer of a porous PAEK medical implant can have a higher crystallinity than the PAEK in the top layer of the PAEK, e.g., a gradient in crystallinity from one side of the medical implant to the other. Other orientations of the crystallinity gradient can also be achieved, e.g., depending on the manufacturing process. For example, a porous PAEK medical implant can have a crystallinity gradient that extends from an inner region of the implant to an outer region of the implant.

[0082] Additionally, individual PAEK lengths may also exhibit a gradient of crystallinity. For example, PAEK lengths in later deposited layers may exhibit a gradient of higher crystallinity PAEK from the interior to the exterior, where crystallinity is lower, e.g., because the exterior surfaces are cooled relatively quickly. Other PAEK lengths, e.g., earlier deposited layers, may exhibit a gradient of increasing crystallinity from the interior to the exterior, e.g., because the exterior surfaces have time to reorganize due to remelting of these layers. In some embodiments, post-lamination annealing can further enhance the crystallinity of the exterior surfaces of the PAEK lengths.

[0083] In some embodiments, the outer surface of the 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 throughout the porous structure of the medical implant, covering substantially all of the outer surface of the PAEK. The coating is chemically bonded to the PAEK. As with uncoated PAEK, the outer surface of at least some of the 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.

[0084] The coating is a thin coating, e.g., thin enough that bone can be directly fixed to the outer surface of the PAEK of the medical implant. The ability to fix bone directly to the PAEK, e.g., rather than to the coating itself, provides mechanical stability. For example, the coating thickness is 1 nm to 80 nm, e.g., 1 nm to 50 nm, 1 nm to 20 nm, or 1 nm to 10 nm.

[0085] 6A and 6B are SEM images of a PEEK medical implant coated with HA. As shown in these images, the HA coating is a crystalline coating with elongated, needle-like crystals with lengths ranging from 50 nm to 250 nm, e.g., 50 nm to 100 nm.

[0086] Specific structural attributes of porous PAEK medical implants, such as the interconnected pore network, 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. Microstructural and nanostructural attributes, including surface crystallinity and surface roughness, contribute to the osteoinductive (e.g., immunomodulatory) behavior of medical implants.

[0087] In some embodiments, a porous PAEK medical implant has multiple regions, each with a different porosity. For example, referring to FIG. 7 , a porous PAEK medical implant 900 includes a first region 902 having a high porosity, e.g., 40%-80% porosity, and a second region 908 having a much lower porosity, e.g., 0%-10% porosity. In the embodiment of FIG. 7 , both regions 902, 908 span all layers of the porous PAEK medical implant (e.g., from the bottom to the top surface of the implant), but in some embodiments, one or more of the multiple regions do not span all layers. In some embodiments, in at least one layer, a continuous length of PAEK connects the two regions 902, 908. This means, for example, that the extrusion of the PAEK length is not interrupted when printing of a region with a different porosity begins.

[0088] The porous PAEK medical implants described herein can be configured for use in a variety of anatomical situations. The porous PAEK medical implant in FIG. 1 is a cervical spine implant. With reference to FIGS. 8A-8D, other types of spinal implants can be porous PAEK medical implants, including posterior lumbar interbody fusion (PLIF, see FIG. 8A), transforaminal lumbar interbody fusion (TLIF, see FIG. 8B), anterior lumbar interbody fusion (ALIF, see FIG. 8C), direct lateral interbody fusion (DLIF, see FIG. 8D), or extra-lateral interbody fusion (XLIF). With reference to FIGS. 9A and 9B, the porous PAEK medical implant can be an extremity implant (FIG. 9A), such as a tibial plateau implant, a cotton implant, or an Evans wedge implant, or a large joint implant (FIG. 9B). The medical implants described herein may be cranial or maxillofacial implants, or may be used to reconstruct bone, such as inner bones, bones of the foot or ankle, bones of the hand or wrist, or other suitable bones.

[0089] Porous PAEK structures can also be used in other medical applications, such as for drug delivery or neurological applications. Porous PAEK structures can also be configured for non-medical applications. For example, porous PAEK structures can be used in aerospace applications, such as aircraft engine components (e.g., for high heat resistance and performance at high temperatures), aircraft exterior components (e.g., for rain erosion resistance), or other aerospace applications (e.g., as a lightweight aluminum replacement). They can also be used in automotive applications or other suitable applications.

[0090] Although porous PAEK structures are referred to herein, such 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, the porous additively manufactured structure can be a composite material, such as a polymer composite, e.g., a layered polymer composite. These structures can contain ceramic or slurries, biologics, cellular materials, or proteins.

[0091] The porous PAEK structures (e.g., medical implants) described herein have mechanical properties suitable for the context in which they are used. For example, porous PAEK medical implants have mechanical properties comparable to physiological bone at the intended implant site. Unless otherwise specified, the mechanical properties described herein were measured in accordance with ASTM F2077 testing standards.

[0092] The porous PAEK structures described herein have a Young's modulus of 0.3 Gpa to 4.0 GPa, for example 0.3 Gpa to 3.0 GPa, 0.8 Gpa to 1.5 GPa, or 1.0 Gpa to 1.2 GPa. This range of Young's modulus is comparable to that of cancellous bone.

[0093] The compressive strength of the porous PAEK structure is at least 20 kN, e.g., 20 kN to 150 kN, 20 kN to 100 kN, 20 kN to 40 kN, or 22 kN to 30 kN. Compressive strengths in this range are significantly higher than the compressive strength of physiological bone (e.g., compressed cancellous bone), e.g., at least 2 times, at least 6 times, e.g., 2 times to 10 times higher.

[0094] The fatigue strength of the porous PAEK structures described herein is 1200 N to 1800 N, for example 1500 N, at 5 Hz for 5 million cycles. The stiffness of the porous PAEK structures described herein is 0.8 Gpa to 1.5 GPa, for example 1.0 Gpa to 1.2 GPa.

[0095] Other mechanical properties of the porous PAEK structure, such as torsion, compression shear, and subsidence, are also comparable to those of physiological bone at the intended implant site.

[0096] Without being bound by theory, it is believed that the crystalline microstructure of the porous PAEK structures described herein, with a semi-amorphous interior surrounded by a crystalline outer surface, contributes to these mechanical properties. For example, the crystallization of the outer surface (discussed further below) that occurs upon cooling of the PAEK after printing creates a surface compression layer, providing strength and stiffness to the PAEK length and, therefore, the entire structure. Additionally, the porous lattice structure, e.g., the TPMS diamond structure with interconnected pores, also contributes to the strength, modulus, and toughness of the structure.

[0097] 10, the porous PAEK medical implants described herein are fabricated using an additive manufacturing system that implements an additive manufacturing process such as fused strand deposition modeling, fused filament fabrication, or fused deposition modeling. As discussed above, the time and temperature profiles of the additive manufacturing process contribute to the nonlinear and non-uniform nature of the continuous lengths of PAEK that make up the medical implant, as well as the surface microstructure of the PAEK.

[0098] The system includes a print head 252 that heats and ejects 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 fed into a supply tube 262 of the print head 252 via an inlet 264 and connected to a supply tube outlet 266 via an internal passage 268. The internal passage 268 of the supply tube 262 has an upstream portion 270 and a downstream portion 272. As the PAEK filament passes through the downstream portion 272 of the supply tube 262, a heater 256 heats the filament to a temperature significantly higher than the melting point of the PAEK, e.g., 50-100°C above the melting point. For example, the heater 256 heats the filament to a temperature between 325°C and 475°C. As a specific example, if the filament is PEEK, which has a melting point of approximately 340°C, the heater 256 heats the filament to a temperature between 400°C and 500°C, e.g., 400°C and 450°C, e.g., 430°C. As explained further below, heating the PAEK to a temperature significantly above its melting point allows the extruded PAEK to remain in a molten state immediately after lamination, which contributes to the nonlinear and non-uniform porous structure described above.

[0099] An upstream portion 270 of the feed tube 262 is cooled by a cooler 254 to regulate the temperature of the PAEK filament as it passes through the feed tube 262. The cooler 254 is spaced upstream from the heater 256, with a gap 276 separating the cooler 254 and the heater 256. In some embodiments, a secondary cooler 278 directly cools the PAEK filament within the feed tube 262.

[0100] Hot zone 280 separates the heat generated by heater 256 from the cooler temperature in the region of cooler 254 and secondary cooler 278. The presence of hot zone 280 allows the PAEK filament to remain in a solid state until it reaches hot zone 280, at which point it begins to transition from a solid to a molten state. This configuration prevents the heat from heater 256 from melting the PAEK filament in the upstream portion 270 of the feed tube, which could cause premature crystallization of the PAEK.

[0101] Molten filaments of PAEK are extruded through a nozzle 260 onto a build plate 290 to form a porous PAEK structure. The build plate 290 is rotated relative to the nozzle 260 as each successive layer of PAEK is formed, e.g., by 20°-60°, e.g., 20°-40°, or 30°-40°, e.g., approximately 36°. This rotation and the loose packing of each layer means that much of the PAEK in the upper layers is unsupported by the layers below. This unsupported porous structure and the temperature profile during extrusion both contribute to the microstructure of the resulting porous PAEK structure.

[0102] The rate at which the PAEK filament is extruded from the nozzle 260 and the rate at which the nozzle 260 moves relative to the build plate 290 during extrusion (referred to as the feed rate) also affect the microstructure of the resulting porous PAEK structure. For example, for a nozzle diameter of 0.2 mm to 0.5 mm, the PAEK extrusion rate can be 2 mm / s to 20 mm / s, e.g., 10 mm / s to 15 mm / s. The feed rate can be 5 mm / s to 20 mm / s, e.g., 8 mm / s to 12 mm / s or 10 mm / s to 20 mm / s. Both faster extrusion rates and faster feed rates result in thinner PAEK bead buildup.

[0103] The ratio of the extrusion rate to the feed rate is called the extrusion ratio. Typically, PAEK filaments are extruded at an extrusion ratio of 0.5 to 4.0, e.g., 0.5 to 2.0 or 0.6 to 1.0. Lower extrusion ratios (e.g., lower extrusion rates for the same feed rate) result in thinner bead buildup, which may exhibit attenuation (e.g., nonlinearity and non-uniform diameter) in unsupported portions of the laminated PAEK.

[0104] For example, the extrusion path can introduce local variations in the microstructure of porous PAEK structures. For example, as the extrusion path turns corners from one row to another, the extruded PAEK undergoes acceleration and deceleration, resulting in a bulge upstream of the corner and a narrowing downstream of the corner. These microstructural variations result in micron-scale roughness in the resulting porous PAEK structure that mimics, for example, the microstructure of physiological bone.

[0105] The printing surface, and the PAEK structure developing thereon, is maintained at a temperature near the glass transition temperature of the PAEK, e.g., 130°C to 160°C. In some embodiments, the temperature of the printing surface is maintained by a reflector 292, which can be composed of a material with passive heat-reflecting properties, can include active heating elements, or both. In some embodiments, the temperature of the printing surface is maintained by a heating layer disposed below the build plate 290 (e.g., on the opposite side of the build plate 290 from the print head 252). In some embodiments, both a reflector and a heating layer are used. The operation of the reflector 292, the heating layer, or both, can be controlled by closed-loop feedback control to maintain the printing surface at a desired temperature.

[0106] Maintaining the printing surface at a temperature near the glass transition temperature of the PAEK allows the printed PAEK to remain in a glassy state, thereby enabling bonding between lengths of PAEK in adjacent layers. For example, when a strand of molten PAEK is extruded from the nozzle 260 of the printhead 252, the molten PAEK can remelt the PAEK in an underlying, previously printed layer, bonding the two PAEK lengths together to form a node. This remelting and bonding is further facilitated by extruding the PAEK at a temperature significantly higher than the melting point of the PAEK. The hot-extruded PAEK remains above its melting point after being extruded from the nozzle 810 long enough to remelt and bond the underlying PAEK.

[0107] Extruding PAEK at temperatures significantly higher than its melting point and maintaining the printing surface near the PAEK's glass transition temperature also allows for the formation of nonlinear and nonuniform PAEK lengths between the nodes of the structure. After the extruded PAEK bonds with the underlying PAEK to form a node, the molten PAEK stretches across an unsupported space before reaching another PAEK support to form another node. This thinning of the PAEK between the nodes creates nonuniformities in its diameter. The PAEK stretches to a smaller diameter between the nodes while remaining at 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 stretching the PAEK also induces twisting of the unsupported PAEK lengths, further contributing to the PAEK's surface microstructure.

[0108] Maintaining the printed surface at a temperature near the glass transition temperature of the PAEK also contributes to the crystalline structure of the resulting PAEK. PAEK 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, allows for crystallization of the outer surface. Furthermore, when the next layer of PAEK is laminated, the nodes of the previously extruded PAEK remelt, further extending the cooling time and contributing to surface crystallization.

[0109] 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, if the medical implant is made of PEEK, which has a glass transition temperature of about 140°C, the porous PEEK medical implant is annealed at a temperature between 150°C and 300°C, e.g., between 150°C and 200°C, for a period of 1 hour to 10 hours. After fabrication, the outer surface of the PAEK in the medical implant has the lamellar surface microstructure described above with respect to Figures 6A-6B.

[0110] In some embodiments, a coating, such as a hydroxyapatite coating, is applied to the surface of the porous PAEK medical implant following the additive manufacturing process and annealing. The coating can be applied by a coating process such as dip coating, immersion coating, or spray coating. The coating is applied to all surfaces of the porous PAEK medical implant, for example, extending throughout the internal porous structure of the medical implant. [Example]

[0111] Unless otherwise noted, all tests were performed on PEEK articles formed by fused filament fabrication with the following parameters:

[0112] (Example 1) Mechanical properties The mechanical properties of the PEEK cervical implants fabricated as described above were tested, including compressive strength, elastic modulus, and fatigue strength. Unless otherwise noted, the mechanical properties described herein were measured in accordance with ASTM F2077 testing standards.

[0113] Referring to Figures 11A and 11B, the compressive strength of the PEEK cervical implant was measured using a static axial compression test. Referring specifically to Figure 11A, the compressive strength of the PEEK cervical implant was found to be greater than 25 kN. This means that the PEEK cervical implant partially fractures when subjected to a 25 kN compressive force. Figure 11B is a photograph of the PEEK cervical implant after application of a 25 kN compressive force, showing that the implant remains largely intact and only partially fractures.

[0114] 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.

[0115] The fatigue strength of PEEK cervical implants was measured using dynamic axial compression testing performed in accordance with ASTM F2077. The PEEK cervical implants survived 5 million cycles of a 1500 N force at 5 Hz and remained structurally intact. Figure 11C shows a photograph of the PEEK cervical implant after the dynamic axial compression test was completed.

[0116] The stiffness of PEEK cervical implants was confirmed during static axial compression testing. PEEK cervical implants tested to Kd = 13,623 N / mm, which is approximately the 75th percentile of FDA published data.

[0117] Further mechanical testing was performed on porous PEEK cervical intervertebral cages without X-ray markers, confirming that the observed mechanical properties were due to the PEEK structure and not the X-ray markers.

[0118] Dynamic axial compression testing was performed on a PEEK cervical intervertebral implant without an X-ray marker. Figure 12A shows a photograph of the implant before testing, and Figure 12B shows a photograph of the implant after 5,000,000 cycles. As shown in the photographs, the dynamic axial compression testing resulted in virtually no mechanical damage. The height measurements for each of the two specimens are shown in Table 1, confirming that the implants were structurally intact.

[0119] [Table 1]

[0120] Drop weight clinical impact testing was also performed on PEEK cervical intervertebral implants without X-ray markers. Samples were tested according to the test parameters shown in Table 2.

[0121] [Table 2]

[0122] The drop weight test results, shown in Table 3, indicate that the implants remained structurally intact.

[0123] [Table 3]

[0124] Example 2: Biological activity of porous PEEK structures The osteogenic potential of PEEK cervical implants with various microstructures and surface chemistries was characterized with respect to the bone formation of human bone marrow stromal cells (hBMSCs). This assay determines whether hBMSCs transform into osteoblasts, a bone-forming cell type, after exposure to a particular surface. This transformation is indicated primarily by surface cell markers and the resulting gene expression and protein production. Materials that demonstrate this cellular transformation are said to have osteogenic potential. As shown in this example, porous PEEK cervical implants were shown to have osteogenic potential in this assay.

[0125] Figure 13 shows the study process flow. On study day zero, hBMSCs were seeded onto four substrates: control tissue culture-grade polystyrene (TCPS), porous PEEK cervical implants (PP) prepared as described above, HA-coated porous PEEK cervical implants (PP-HA), and solid PEEK blocks (SP). Cells were cultured for 14 days, after which the cultures were exposed to fresh conditioned medium for 24 hours. Cell layer lysates were extracted and assayed for products including osteocalcin, osteopontin, osteoprotegerin, vascular endothelial growth factor (VEGF), and DNA. Interleukins, including IL-4, IL-10, IL-6, BMP-2, BMP-4, BgLAP, RUNX-2, and SP7, were also assayed.

[0126] Figure 14 shows the results of an hBMSC assay demonstrating the effect of various surface chemistries and microstructures on the osteogenic potential of the constructs, as indicated by DNA concentration and protein production, including osteocalcin, osteopontin, osteoprotegerin, and vascular endothelial growth factor 165. Figure 15 shows interleukin production, again demonstrating the effect of surface chemistry and microstructure on the osteogenic potential of the constructs. The top and bottom panels of Figure 15 represent the results of two different experiments, showing generally consistent results. Referring to Figure 16, the hBMSC cultures described above were also analyzed to characterize gene expression to further demonstrate the osteogenic potential of the constructs.

[0127] A summary of the results and their significance is shown in Table 4.

[0128] [Table 4]

[0129] Osteocalcin is a mineralization protein. Its presence indicates the presence of osteoblasts and therefore an environment that promotes bone formation. These results demonstrate upregulation of osteocalcin. Cultures from all three PEEK samples exhibit higher osteocalcin concentrations than TCPS cultures. Osteopontin and osteoprotegerin are proteins that promote bone formation, specifically regulating the upregulation of osteoclasts. As shown in these plots, cultures from all three PEEK samples have higher concentrations of osteopontin and osteoprotegerin than TCPS cultures, while porous PEEK (PP) cultures have significantly higher concentrations of each protein than the other PEEK samples. Vascular endothelial growth factor (VEGF) contributes to angiogenesis. VEGF concentrations in cultures from all three PEEK samples were higher than in TCPS cultures, with the two porous PEEK cultures (PP and PP-HA) exhibiting the highest concentrations. These results are a positive indication of the osteogenic potential of porous PEEK.

[0130] Gene expression results were also a positive indicator of the osteogenic potential of porous PEEK. The final group (BMP-2, -4, BgLAP, Runx2, SP7) all showed either increased or no change in expression.

[0131] Overall, the upregulation of OCN, OPN, OPG, VEGF, IL-4, and IL-10, and the concomitant downregulation of IL-6 compared to solid PEEK, indicate that both porous PEEK (PP) and HA-coated porous PEEK (PP-HA) exhibit osteogenic potential. While different proteins may be expressed at different times during physiological bone formation, the results of this cellular (in vitro) assay are consistent with the behavior of known bone-forming (osteogenic) materials.

[0132] Referring to Figure 17, in another experiment, a macrophage polarization assay was performed to characterize the immunomodulatory capabilities of the implant. The macrophage polarization assay verifies naive macrophages (e.g., present early in inflammation, injury, or surgery) that respond to specific surfaces. M1 macrophages remove debris and induce inflammatory cytokines, while macrophages that transition to the M2 phenotype are pro-regenerative macrophages. M1 phenotype macrophages exhibit specific gene expression that leads to the formation of fibrous tissue. M2 phenotype macrophages release various proteins that result in pro-regenerative and anti-inflammatory regeneration, which leads to bone formation.

[0133] Indicators of inflammatory M1 macrophages result in the expression of iNOS, TNF-α, IL-6, and IL-1β. Indicators of pro-regenerative (anti-inflammatory) M2 macrophages result in the expression of Arg1, Mrc1, TGF-β1, IL-4, and VEGF. Consistent with this behavior, as shown below, PP and PP-HA surfaces exhibited up- and down-regulation of genes and proteins confirming the transition to the M2 phenotype, demonstrating the immunomodulatory behavior of the PP and PP-HA structures.

[0134] At the beginning of the process, macrophages were harvested and allowed to grow for 7 days. During this time, the culture medium was replaced with medium containing macrophage colony-stimulating factor (MCSF). After 7 days of macrophage growth, the macrophages were seeded and dropped onto the MCSF-containing surface. Macrophage experiments were then performed. Specifically, the culture medium was replaced with fresh medium two days after seeding, and five test groups were analyzed: porous PEEK (PP), porous PEEK with an HA coating (PP-HA), solid PEEK (SP), and two control groups treated with M1 and M2, respectively. None of the test groups received MCSF.

[0135] The results of an assay showing the inflammatory response (e.g., M1 expression) are shown in Figure 18, demonstrating that porous PEEK suppresses the M1 inflammatory phase, particularly compared to solid PEEK. The results of an assay showing the tissue repair response (e.g., M2 expression) are shown in Figure 19, demonstrating that porous PEEK promotes M2 expression (leading to enhanced regeneration and bone formation). Furthermore, assays were performed 7 days after seeding. These results, shown in Figures 2019 and 2120, are generally consistent with the day 2 results in Figures 18 and 19. That is, porous PEEK suppresses the inflammatory phase and promotes M2 expression.

[0136] These results demonstrate that the up- and down-regulation of genes and proteins by PP and PP-HA samples, along with the expected gene and protein expression / production, polarizes macrophages toward a pro-regenerative M2 phenotype. These results also demonstrate the suppression and down-regulation of pro-inflammatory genes and proteins of the M1 phenotype.

[0137] These results are generally consistent with the hBMSC assay described above, with the PEEK samples exhibiting more markers of bone growth than the control samples. Taken together, these validated cell assays confirm that porous PEEK fabricated according to the fused filament fabrication process described above and porous PEEK coated with HA exhibit both osteogenic potential and immunomodulatory activity (immuno-osteogenesis), behavior that is generally uncommon for PEEK surfaces.

[0138] Notably, the above-mentioned assays favored materials known to be hydrophilic, physiological (e.g., Ca / P chemistry), and possess submicron surface morphology, acicular morphology, and submicron pore size. The porous PEEK implants described herein possess these characteristics. Notably, these results demonstrate that porous PEEK implants without an HA coating, such as those imparted by the fused filament fabrication process, still possess sufficient properties to perform well in these assays.

[0139] The bone formation experiments described above were carried out according to the following process: Human female MSCs (23-year-old Caucasian) were cultured in MSC growth medium (GM) until confluent before seeding onto the test surfaces. Test discs from each group were placed in a 24-well plate at 10,000 cells / cm. 2 MSCs were seeded at a density of 0.5 mL per well (20,000 cells / mL / well). GM was replaced 24 hours after seeding and then every 48 hours for 14 days. At the beginning of day 14, the medium was replaced with fresh GM, and cells were cultured for 24 hours before harvesting. At harvest, the medium was collected and aliquoted into 1.5 mL Eppendorf centrifuge tubes. MSC-containing wells were washed twice with 1 mL of phosphate-buffered saline (PBS), placed in 0.5 mL of 0.05% Triton-X100, and frozen at -80°C for biological assays.

[0140] To analyze DNA content, cell layers were lysed by sonication (40 V, 10 s / well), and total DNA content was measured by fluorescence. Protein and cytokine production levels in the conditioned medium were quantified by enzyme-linked immunosorbent assay according to the manufacturer's protocol. Proteins analyzed included osteocalcin (OCN), osteoprotegerin (OPG), bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 4 (BMP4), bone morphogenetic protein 7 (BMP7), interleukin 6 (IL6), interleukin 4 (IL4), and interleukin 10 (IL10).

[0141] The following experimental protocol was performed to characterize the macrophage polarization response to various implants using primary naive bone marrow-derived macrophages.

[0142] 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 30 ng / mL macrophage colony-stimulating factor (M-CSF). These cultures were compared for M1 and M2-induced macrophage phenotypes. M1 was induced by adding interferon-γ (IFN-γ) and lipopolysaccharide (LPS) to 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. Secreted inflammatory markers, TNFα, IL-1, IL-4, IL-6, IL-10, and IL-13, were quantified according to the implant material. Gene expression was measured for inducible nitric oxide synthase (iNOS), a marker of the M1 phenotype, and arginine-1 (Arg1), a marker of the M2 phenotype.

[0143] Bone marrow was harvested as follows: Primary mouse macrophages were isolated from the femurs of 6-8 week-old male C57BL / 6 mice. Bone marrow cells were flushed from the mouse femurs using Dulbecco's phosphate-buffered saline. Red blood cells were lysed from the bone marrow extract using ACK lysis buffer. Cells were collected and pooled to generate a mixed population of mouse cells. Cells were counted and plated at a density of 500,000 cells / mL in 10 mL of RPMI 1640 medium (supplemented with 10% FBS, 50 U / mL penicillin, 50 μg / mL streptomycin, and 30 ng / mL macrophage colony-stimulating factor) at 75 cm . 2The cells were seeded into flasks and cultured at 37°C, 5% CO2, and 100% humidity. To generate a homogenous naive macrophage population, macrophages were passaged using Accutase 7 days after seeding to a density of 20,000 cells / cm. 2 were seeded on a specific surface at a density of .

[0144] For surface seeding, PP, PP-HA, and SP coupons were washed and γ-irradiated. Naive macrophages in RPMI 1640 culture medium supplemented with 30 ng / mL M-CSF were seeded on the surfaces and compared with the phenotypes of M1- and M2-induced macrophages seeded on TCPS. The M1 phenotype was induced by adding IFN-γ (20 ng / mL) and LPS (100 ng / mL) to the growth medium at the time of seeding. The M2 phenotype was induced using IL-4 / IL-13 (20 ng / mL each) at the time of seeding. Macrophages were plated at 10,000 cells / cm on the surface of a 24-well plate. 2 The cells were seeded at a density of 20,000 cells / mL / well. RPMI 1640 supplemented with M-CSF was replaced 24 hours before harvesting.

[0145] Twenty-four hours after treatment, conditioned medium was collected and aliquoted into 1.5 mL Eppendorf centrifuge tubes. Wells were washed twice with 1 mL of PBS and aspirated. 1 mL of 0.05% Triton-X was added and frozen overnight at -20°C. Secreted inflammatory markers TNFα, IL1β, IL4, IL6, IL10, and IL13 were quantified in response to the surface using ELISA according to the manufacturer's protocol. Immunoassay results were normalized to the dsDNA content in the cell lysates. Culture medium was analyzed by ELISA according to the manufacturer's protocol.

[0146] For PCR harvest, cells were lysed and homogenized with QiaZol for isolation using spin columns. Cell monolayers were washed with PBS, lysed with 0.05% Triton X-100, and homogenized by sonication at 40V for 10 seconds per well. RNAeasy spin columns were run according to the manufacturer's instructions and quantified using a Take3 spectrometer (Qiagen). mRNA was measured for iNos (M1) and Arg1 (M2) and normalized to Gapdh.

[0147] Example 3: Live animal experiments on porous PEEK implants Various types of PEEK implants, including porous PEEK implants, HA-coated porous PEEK implants, and solid PEEK implants, were implanted in aged ewes (4-5 years old). The implants were 25 mm x 6 mm outer diameter. The implants were evaluated for bone ingrowth at the bone-implant interface 4 and 12 weeks after surgery. Surface characterization of the implants was performed before implantation using light and scanning electron microscopy. The implanted sites in the cortical and cancellous bone, as well as the mechanical properties of the implants in the cortical bone site, were evaluated over time by radiography. New bone formation was assessed over time based on routine PMMA histology in the cortical and cancellous bone sites.

[0148] Implants were inserted into the cancellous bone of the distal femur and proximal tibia using a press fit technique and into the cortical bone of the tibia using a line-to-line technique. Samples were examined using a standard shear stress push-out test, as well as histological and morphological examinations, 4 and 12 weeks after surgery.

[0149] At the designated time points, each animal was euthanized and examined and dissected according to SOP-28. Right and left hind limbs were harvested and photographed and radiographed. The tibia and femur were scanned using a Siemens Inveon Micro CT to obtain high-resolution scans of the bone-implant interface and to assess osseointegration. The cancellous bone was isolated and fixed in cold phosphate-buffered formalin. The cortical bone was isolated and cut in the sagittal plane to isolate medial and lateral specimens for push-out testing.

[0150] Cortical and cancellous specimens were isolated and immediately processed for PMMA histology. Specimens were placed in 10% buffered formalin and dehydrated in ascending concentrations of ethanol for embedding in polymethyl methacrylate (PMMA) according to SOP-24. Embedded cortical and cancellous bone implants were cut along the long axis of the implant using a Leica SP 1600 Microtome according to SOP-35. At least two thin sections (15-20 microns) were cut from each embedded implant and stained with methylene blue and basic fuchsin, which stained bone pink and fibrous tissue blue or purple.

[0151] Figures 22A and 22B include images showing the histology of the HA-coated porous PEEK implant four weeks after implantation. With particular reference to Figure 22B, the pale translucent bands in the implant image indicate that the PEEK is amorphous, while the opaque areas indicate that it is crystalline. Figure 23 includes images showing the histology 12 weeks after implantation. These images show bone infiltration and osteointegration throughout the implant, demonstrating the implant's effectiveness in promoting osteoconduction, osteointegration, and bone formation.

[0152] Figure 24 includes additional images showing the histology of the HA-coated porous PEEK implant 12 weeks after implantation. These images show the layered structure of the PEEK within the implant itself. The pale translucent bands are amorphous regions, and the opaque regions are crystalline regions. Cortical bone, generally stained purple, has grown through the implant without significant fibrous tissue growth. For example, blood vessels formed from epithelial cells are present, allowing bone marrow, blood, etc. to be supplied to the bone. Osteoblasts and osteocytes are also present, indicating healthy new bone growth.

[0153] Figures 25A and 25B contain images showing the histology of porous PEEK implants with an HA coating (Figure 25A) and without an HA coating (Figure 25B) 12 weeks after implantation in different animals, showing new bone growth throughout the porous structure of both implants.

[0154] Figure 26 shows a histological image of a porous PEEK implant without an HA coating after 12 weeks implanted in a metaphyseal region, showing cancellous bone growth throughout the porous structure of the implant.

[0155] Figures 27-28 show histological images of ovine porous PAEK implants after 12 weeks, demonstrating the quality of bone formation within the implants. Figure 27 contains transmitted light images, and Figure 28 contains stereomicroscope images. These images demonstrate the formation of bone structures such as blood vessels, bone cells, and rounded osteon formation within the implants.

[0156] Figure 29 shows micro-computed tomography (micro-CT) images of HA-coated porous PEEK implants taken 12 weeks after implantation. These images show bone growth around and through the implants. For example, healed bone growth can be seen on the outside and inside of the bone where the drill holes were made to insert the implants. Specifically, the white areas, e.g., area 60, are the original cortical bone, while the gray areas, e.g., area 62, are new bone growth. These images also show bone growth throughout the pores of the implants. The implants are brown, while the bone that permeates the porous structure of the implants is white.

[0157] In embodiment 1, an article includes multiple layers of polyaryletherketone (PAEK), each layer composed of a continuous length of PAEK, the continuous length of PAEK in at least one layer including an interior and an exterior surface including crystalline regions, the exterior surface having a higher 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 that layer, or both. The multiple layers of PAEK define a network of interconnected pores.

[0158] In a second embodiment, which can be combined with the first embodiment, the continuous lengths of PAEK in each layer are arranged in an aligned manner.

[0159] In embodiment 3, which can be combined with embodiment 2, the rows have a serpentine, curved, or zigzag configuration.

[0160] In embodiment 4, which can be combined with either embodiment 2 or 3, the rows of each layer are rotated relative to the rows of adjacent layers.

[0161] In a fifth embodiment, which can be combined with the fourth embodiment, each row of layers is rotated by 20 to 60 degrees relative to the row of adjacent layers.

[0162] In a sixth embodiment, which can be combined with the fifth embodiment, the rows of each layer are rotated 36° relative to the rows of the adjacent layers.

[0163] In embodiment 7, which can be combined with any of embodiments 1 to 6, the cross-sectional area of ​​the continuous length of PAEK is non-uniform within each layer.

[0164] In embodiment 8, which can be combined with any of embodiments 1 to 7, the continuous length of PAEK also extends between adjacent layers.

[0165] In a ninth embodiment which may be combined with any of the first to eighth embodiments, each layer defines a plane, and a portion of the continuous length of PAEK in each layer extends outside the plane defined by that layer.

[0166] In embodiment 10, which can be combined with any of embodiments 1 to 9, the continuous length of PAEK in each layer intersects the continuous length of PAEK in the adjacent layer at a node.

[0167] In an eleventh embodiment, which can be combined with the tenth embodiment, the continuous length of PAEK extending between adjacent nodes is non-linear.

[0168] In embodiment 12, which can be combined with any of embodiments 1 to 11, the outer surface of the continuous length of PAAK comprises crystalline domains separated by amorphous regions.

[0169] In embodiment 13, which can be combined with any of embodiments 1 to 12, the outer surface of the continuous length of PAEK comprises a lamellar surface microstructure.

[0170] In embodiment 14, which can be combined with embodiment 13, the lamellar surface microstructure has a characteristic dimension of 4 to 6 nm.

[0171] In embodiment 15, which can be combined with embodiment 14, the lamellar surface microstructure forms spheres on the outer surface of the continuous length of PAEK.

[0172] In embodiment 16, which can be combined with embodiment 15, the spheroids have a characteristic dimension of 4 to 6 μm.

[0173] In embodiment 17, which can be combined with any of embodiments 1 to 16, the continuous lengths of PAEK in the layers of the first set of layers have a different crystallinity than the continuous lengths of PAEK in the layers of the second set of layers.

[0174] In embodiment 18, which can be combined with any of embodiments 1 to 17, the layers of PAEK define a trabecular structure.

[0175] In embodiment 19, which can be combined with any of embodiments 1 to 18, the multiple layers of PAEK form a triply periodic minimal surface (TPMS) structure that defines a network of interconnected pores.

[0176] In embodiment 20, which can be combined with embodiment 19, multiple layers of PAEK form a TPMS diamond structure.

[0177] In embodiment 21 which can be combined with any of embodiments 1 to 20, the surface roughness of the continuous length of PAEK is 0.5 μm to 3.0 μm.

[0178] In embodiment 22 which can be combined with embodiment 21, the surface roughness of the continuous length of PAEK is 1 μm to 1.5 μm.

[0179] In embodiment 23, which can be combined with any of embodiments 1 to 22, the article has a Young's modulus of 0.3 GPa to 4.0 GPa.

[0180] In embodiment 24, which can be combined with embodiment 23, the Young's modulus of the article is 0.8 GPa to 1.5 GPa.

[0181] In embodiment 25, which can be combined with any of embodiments 1 to 24, the article has a compressive strength of at least 20 kN.

[0182] In embodiment 26 which can be combined with embodiment 25, the article has a compressive strength of 20 kN to 150 kN.

[0183] In embodiment 27, which can be combined with embodiment 26, the article has a compressive strength of 20 kN to 100 kN.

[0184] In embodiment 28, which can be combined with embodiment 27, the article has a compressive strength of 20 kN to 30 kN.

[0185] In embodiment 29, which can be combined with any of embodiments 1 to 28, the fatigue strength of the article measured at 5 Hz for 5M cycles is 1200N to 1800N.

[0186] In embodiment 30, which can be combined with any of embodiments 1 to 29, the stiffness of the article is 0.8 GPa to 1.5 GPa.

[0187] In embodiment 31 which can be combined with any of embodiments 1 to 30, the article comprises a coating comprising hydroxyapatite applied to the outer surface of the continuous length of PAEK.

[0188] In embodiment 32, which can be combined with embodiment 31, the coating thickness is 1 nm to 80 nm.

[0189] In embodiment 33, which can be combined with embodiment 32, the coating thickness is 1 nm to 50 nm.

[0190] In embodiment 34, which can be combined with embodiment 33, the coating thickness is 1 nm to 20 nm.

[0191] In embodiment 35, which can be combined with any of embodiments 1 to 34, the continuous length of PAEK has a crystallinity of 20% to 60% by volume.

[0192] In embodiment 36, which can be combined with embodiment 35, the continuous length of PAEK has a crystallinity of 30% to 50% by volume.

[0193] In embodiment 37, which can be combined with any of embodiments 1 to 36, the article has a porosity of 40-80%.

[0194] In embodiment 38, which can be combined with any of embodiments 1 to 37, the pore size is between 100 μm and 1 mm.

[0195] In embodiment 39, which can be combined with embodiment 38, the pore size is between 100 μm and 700 μm.

[0196] In embodiment 40, which can be combined with any of embodiments 1 to 39, the average size of the pores is between 220 μm and 280 μm.

[0197] In embodiment 41 which can be combined with any of embodiments 1 to 40, the PAEK comprises polyetheretherketone (PEEK).

[0198] In embodiment 42, which can be combined with any of embodiments 1 to 41, the multiple layers of PAEK define 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 a portion of the multiple layers.

[0199] In embodiment 43, which can be combined with embodiment 42, a continuous length of PAEK extends between the first region and the second region.

[0200] In embodiment 44, which can be combined with any of embodiments 1 to 43, continuous lengths of PAEK are layered by additive manufacturing.

[0201] In embodiment 45, which can be combined with embodiment 44, continuous lengths of PAEK are laminated by melt strand manufacturing.

[0202] In embodiment 46 which can be combined with any of embodiments 1 to 45, the article comprises a medical implant.

[0203] In embodiment 47, which can be combined with embodiment 46, the medical implant is osteoconductive.

[0204] In embodiment 48, which can be combined with embodiment 46 or 47, the medical implant is osteointegrative.

[0205] In embodiment 49, which can be combined with any of embodiments 46 to 48, the medical implant is osteogenic.

[0206] In embodiment 51, a medical implant includes multiple layers of PAEK laminated by fused strand fabrication, each layer consisting of a continuous length of PAEK arranged in an aligned manner, the continuous length of PAEK extending between adjacent layers, the continuous length of PAEK in at least one layer including an interior and an exterior surface comprising crystalline regions, the crystallinity of the exterior surface being higher than the crystallinity of the interior, the cross-sectional area of ​​the continuous length of PAEK being non-uniform within each row, the rows in each layer being rotated relative to the rows in each adjacent layer, forming a TPMS diamond structure defining a network of interconnected pores such that the porosity of the medical implant is 50-70%, and the medical implant is osteoconductive.

[0207] In embodiment 52, which can be combined with embodiment 51, the medical implant comprises a cervical implant.

[0208] In embodiment 53, which can be combined with embodiment 51 or 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.

[0209] In embodiment 54, which can be combined with any of embodiments 51 to 53, the medical implant comprises a joint implant.

[0210] In embodiment 55, the medical implant comprises: extruding a filament of PAEK from a nozzle of an additive manufacturing tool to deposit a plurality of layers of PAEK, each layer comprising a continuous length of PAEK; annealing the stacked layers to induce crystallization of an outer surface region of the continuous length of PAEK, the outer surface having a higher crystallinity than the interior of the continuous length of PAEK; The multiple layers of PAEK are fabricated by a process that includes the steps of:

[0211] In embodiment 56, which can be combined with embodiment 55, the method including the step of extruding filaments of PAEK includes forming continuous lengths of aligned PAEK in each layer.

[0212] In embodiment 57, which can be combined with embodiment 55 or 56, the method includes continuously extruding a filament of PAEK to form adjacent layers, with a continuous length of PAEK extending between the adjacent layers.

[0213] In embodiment 58, which can be combined with any of embodiments 55 to 57, the method includes extruding a filament of PAEK such that each layer defines a plane and a portion of the continuous length of PAEK extends outside the plane defined by that layer.

[0214] In embodiment 59, which can be combined with any of embodiments 55 to 58, the method includes extruding filaments of PAEK such that a continuous length of PAEK in each layer intersects with a continuous length of PAEK in an adjacent layer at a node.

[0215] In embodiment 60, which can be combined with embodiment 59, the continuous length of PAEK extending between adjacent nodes is non-linear.

[0216] In embodiment 61 which can be combined with any of embodiments 55 to 60, the method includes extruding a filament of PAEK such that the continuous length of PAEK has a non-uniform cross-sectional area within each layer.

[0217] In embodiment 62, which can be combined with any of embodiments 55 to 61, the method includes extruding a filament of PAEK such that a plurality of layers form a triple periodic minimal surface (TPMS) structure that defines a network of interconnected pores.

[0218] In embodiment 63, which can be combined with embodiment 62, the multiple layers form a TPMS diamond structure.

[0219] In embodiment 64, which can be combined with any of embodiments 55 to 63, the method includes rotating the additive manufacturing tool after depositing each layer of PAEK.

[0220] In embodiment 65, which can be combined with embodiment 64, the method includes rotating the additive manufacturing tool by 20 to 60 degrees after depositing each layer.

[0221] In embodiment 66, which can be combined with any of embodiments 55 to 65, the method includes heating the nozzle of the production tool to a temperature of 325 to 475°C.

[0222] In embodiment 67, which can be combined with embodiment 66, the method includes heating the nozzle to a temperature of 400 to 450°C.

[0223] In embodiment 68, which can be combined with any of embodiments 55 to 67, the step of extruding a filament of PAEK includes laminating the first layer on a heated platform.

[0224] In embodiment 69, which can be combined with any of embodiments 55 to 68, the method includes extruding a filament of PAEK at an extrusion rate of 10 to 15 mm / s.

[0225] In embodiment 70, which can be combined with any of embodiments 55 to 69, the method includes moving the nozzle relative to the deposited layer at a feed speed of 5 to 15 mm / s.

[0226] In embodiment 71 which may be combined with any of embodiments 55 to 57, the method includes extruding filaments of PAEK at an extrusion ratio of 0.5 to 4.0, where the extrusion ratio is the ratio of the extrusion flow rate of the PAEK to the moving speed of the nozzle relative to the laminate layer.

[0227] In embodiment 72, which can be combined with embodiment 71, the method includes extruding filaments of PAEK at an extrusion ratio of 0.5 to 2.0.

[0228] In embodiment 73, which can be combined with embodiment 72, the method includes extruding filaments of PAEK at an extrusion ratio of 0.6 to 1.0.

[0229] In embodiment 74, which can be combined with any of embodiments 55 to 73, the method includes annealing the stacked layers at a temperature below the glass transition temperature of the PAEK.

[0230] In embodiment 75, which can be combined with embodiment 74, annealing the stacked layers includes forming a lamellar surface microstructure on the outer surface of the continuous length of PAEK.

[0231] In embodiment 76 which can be combined with any of embodiments 55 to 75, the method includes applying a coating comprising hydroxyapatite to the outer surface of the continuous length of PAEK.

[0232] In embodiment 77, which can be combined with embodiment 76, the step of applying the coating includes applying the coating by dip coating, immersion coating, or spray coating.

[0233] In embodiment 78, which can be combined with any of embodiments 55 to 77, the method includes extruding filaments of PAEK using a melt strand lamination process.

[0234] In embodiment 79, which can be combined with any of embodiments 55 to 77, the method includes extruding a filament of PAEK using a fused filament fabrication process.

[0235] In embodiment 80, which can be combined with any of embodiments 55 to 77, the method includes extruding filaments of PAEK using fused deposition modeling.

[0236] In embodiment 81, which can be combined with any of embodiments 55 to 80, the method 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, both of the first region and the second region spanning at least a portion of the plurality of layers.

[0237] In embodiment 82, which can be combined with embodiment 81, a continuous length of PAEK extends between the first region and the second region.

[0238] While particular embodiments of the inventive subject matter have been described, other embodiments are within the scope of the following claims. [Explanation of symbols]

[0239] 100 Medical Implants 102 columns 104 pores 200 layers 202 continuous lengths of PAEK 204 continuous lengths of PAEK Column 206 208 Arrow 210 layers 218 Arrow 220 nodes 252 print head 254 Cooler 256 Heater 260 nozzles 262 Supply Tube 264 Entrance 266 Exit 268 Internal passage 270 Upstream section 272 Downstream section 276 Gap 278 Secondary Cooler 280 Hot Zone 290 build plate 292 Reflector 300 pores 900 Porous PAEK Medical Implants 902 First Area 908 Second Area

Claims

1. 1. An article comprising a plurality of layers of polyaryletherketone (PAEK), each layer being composed of a continuous strand of PAEK, the continuous strand of PAEK in at least one layer comprising: Inside and an outer surface including crystalline regions, wherein the crystallinity of the outer surface is higher than the crystallinity of the interior; The cross-sectional area of ​​the continuous strands of PAEK is non-uniform within each layer; and An article in which the multiple layers of PAEK define a network of interconnected pores.

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

3. 3. The article of claim 2, wherein each row of layers is rotated 20 to 60 degrees relative to the row of adjacent layers.

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

5. 10. The article of claim 1, wherein each layer defines a surface, and a portion of the continuous strands of PAEK in each layer extend outwardly from the surface defined by that layer.

6. 10. The article of claim 1, wherein the continuous strands of PAEK in each layer intersect with the continuous strands of PAEK in an adjacent layer at nodes, and the continuous strands of PAEK extending between adjacent nodes are non-linear.

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

8. 10. The article of claim 1, wherein the outer surface of the continuous strands of PAEK comprises a lamellar surface microstructure, the lamellar surface microstructure having a characteristic dimension of 4 to 6 nm.

9. 9. The article of claim 8, wherein the lamellar surface microstructure forms spheroids on the outer surface of the continuous strands of PAEK, the spheroids having a characteristic dimension of 4 to 6 μm.

10. 10. The article of claim 1, wherein the continuous strands of PAEK in the layers of a first set of the plurality of layers have a different crystallinity than the continuous strands of PAEK in the layers of a second set of the plurality of layers.

11. The article of claim 1 , wherein the multiple layers of PAEK define a trabecular structure.

12. 10. The article of claim 1, wherein the multiple layers of PAEK form a triply periodic minimal surface (TPMS) structure that defines a network of interconnected pores.

13. 10. The article of claim 1, wherein the surface roughness of the continuous strand of PAEK is from 0.5 μm to 3.0 μm.

14. 10. The article of claim 1, wherein the article has a Young's modulus of 0.3 GPa to 4.0 GPa.

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

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

17. The article of claim 1 , wherein the continuous strands of PAEK have a crystallinity of from 20% to 60% by volume.

18. The article of claim 1 having a porosity of 40 to 80%.

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

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

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

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

23. an opening defined through the article, said opening extending from a first surface to an opposite second surface of the article; The article of claim 1 , wherein the article comprises a plurality of X-ray markers, each marker extending from the first surface to the second surface of the article.

24. An article as described in claim 1, wherein when the article is implanted into a patient, the lamellar surface microstructure of the continuous strands of PAEK and the trabecular structure of the multiple layers of PAEK allow bone cells to enter and grow within the implanted article.

25. 10. The article of claim 1, wherein the average pore size is from 50 μm to 1 mm.

26. 26. The article of claim 25, wherein the average pore size is from 220 μm to 280 μm.

27. 13. The article of claim 12, wherein the multiple layers of PAEK form a TPMS diamond structure that defines a network of interconnected pores.

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