Porous polyether-ether-ketone (PEEK) scaffolds and methods of making and use thereof

Abstract

The disclosed subject matter relates to porous polyether-ether-ketone (PEEK) scaffolds, and methods of making and use thereof. For example, described herein are porous polyether-ether-ketone (PEEK) scaffolds comprising a continuous polyether-ether-ketone (PEEK) phase permeated by a continuous pore phase. In some examples, the continuous pore phase comprises a plurality of pores having an average pore size of from 20 to 600 micrometers (microns, μm); the plurality of pores have a concave shape; the porous PEEK scaffold has a porosity of from 40% to 90%; the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa; the porous PEEK scaffold has a compressive modulus of from 50 to 150 MPa; or a combination thereof. Also disclosed herein are methods of making any of the porous polyether-ether-ketone (PEEK) scaffolds disclosed herein. For example, the method comprises forming an immiscible co-continuous blend, annealing, gas saturation, solid state foaming, and leaching.

Description

[0001] POROUS POLYETHER-ETHER-KETONE (PEEK) SCAFFOLDS AND METHODS OF MAKING AND USE THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 536,995 filed September 7, 2023, which is hereby incorporated herein by reference in its entirety.

[0004] BACKGROUND

[0005] Poly-ether-ether-ketone (PEEK) is a popular candidate for medical implants due to its biocompatibility, mechanical strength, and X-ray transparency. However, there is a lack of effective fabrication methods to create biomimetic porous structure in PEEK to promote bone ingrowth. The devices, methods, and systems discussed herein address these and other needs.

[0006] SUMMARY

[0007] In accordance with the purposes of the disclosed devices, methods, and systems as embodied and broadly described herein, the disclosed subject matter relates to porous polyether- ether-ketone (PEEK) scaffolds and methods of making and use thereof.

[0008] For example, described herein are porous polyether-ether-ketone (PEEK) scaffolds comprising a continuous polyether-ether-ketone (PEEK) phase permeated by a continuous pore phase. In some examples, the continuous pore phase comprises a plurality of pores, the plurality of pores having an average pore size of from 20 to 600 micrometers (microns, pm). In some examples, the plurality of pores have a concave shape. In some examples, the porous PEEK scaffold has a porosity of from 40% to 90%. In some examples, the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa. In some examples, the porous PEEK scaffold has a compressive modulus of from 50 to 150 MPa.

[0009] In some examples, the plurality of pores have an average pore size of from 10 to 600 micrometers. In some examples, the plurality of pores have an average pore size of from 20 to 500 micrometers. In some examples, the plurality of pores have an average pore size of from 100 to 400 micrometers. In some examples, the plurality of pores have an average pore size of from 100 to 300 micrometers.

[0010] In some examples, the plurality of pores have an average pore size that varies across a dimension of the porous PEEK scaffold, such that the plurality of pores has an average pore size gradient from an initial average pore size to a final average pore size. In some examples, the average pore size gradient comprises a radial gradient, a linear gradient, a stepped gradient, an exponential gradient, a logarithmic gradient, or a combination thereof. In some examples, the porous PEEK scaffold has a porosity of from 40% to 70%. In some examples, the porous PEEK scaffold has a porosity of from 40% to 65%. In some examples, the porous PEEK scaffold has a porosity of from 50% to 70%.

[0011] In some examples, the porous PEEK scaffold has a compressive strength of from 8 to 26 MPa.

[0012] In some examples, the porous PEEK scaffold is biocompatible, biomimetic, or a combination thereof.

[0013] In some examples, the porous PEEK scaffold further comprises a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof.

[0014] In some examples, the porous PEEK scaffold further comprises a mineral, such as hydroxyapatite (HA), mixed in the matrix or coated on the inner surface of the pores, for example to improve biocompatibility and / or cell attachment.

[0015] Also disclosed herein are methods of use of any of the porous PEEK scaffolds described herein. In some examples, the method comprises using the porous PEEK scaffold as a tissue engineering scaffold. In some examples, the method comprises using the porous PEEK scaffold as a bone implant, such as a trabecular bone implant. In some examples, the method comprises using the porous PEEK scaffold as a cervical disc spacer or cage. In some examples, the method comprises assembling the porous PEEK scaffold together with a solid PEEK structure to fabricate an implant, such as a bone implant, for example a cervical disc spacer. In some examples, the method comprises assembling the porous PEEK scaffold together with a 3D printed structure, which can be dense or porous, to fabricate a customized implant, such as a bone implant, for example a cervical disc spacer. In some examples, the method comprises using the porous PEEK scaffold as a filter, as a substrate for biochemical sensing, or a combination thereof.

[0016] Also disclosed herein are articles of manufacture or devices comprising any of the porous PEEK scaffolds described herein. In some examples, the article or device comprises a tissue engineering scaffold. In some examples, the article or device comprises a bone implant, such as a trabecular bone implant. In some examples, the article or device comprises a cervical disc spacer or cage. In some examples, the article or device comprises the porous PEEK scaffold assembled together with a solid PEEK structure, the assembly being an implant, such as a bone implant, for example a cervical disc spacer. In some examples, the article or device comprises the porous PEEK scaffold assembled together with a 3D printed structure, which can be dense or porous, the assembly being a customized implant, such as a bone implant, for example a cervical disc spacer. In some examples, the article or device comprises a filter, a substrate for biochemical sensing, or a combination thereof.

[0017] Also disclosed herein are methods of making any of the porous polyether-ether-ketone (PEEK) scaffolds disclosed herein. For example, the method comprises blending polyether- ether-ketone (PEEK) and polyether sulfone (PES) together at a blending temperature to form an immiscible co-continuous blend comprising PEEK and PES, wherein the immiscible co- continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 30:70 to 70:30. In some examples, the method further comprises annealing the immiscible blend at an annealing temperature, thereby forming an annealed composition. In some examples, the method further comprises saturating the annealed composition with a gas, thereby forming a gas saturated composition. In some examples, the method further comprises solid state foaming the gas saturated composition, thereby forming a foamed composition, wherein the foamed composition comprises a foamed PES phase and a substantially unfoamed PEEK phase. In some examples, the method further comprises exposing the foamed composition to a solvent thereby leaching the foamed PES phase to form the porous PEEK scaffold.

[0018] In some examples, the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 40:60 to 70:30. In some examples, the immiscible co- continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 40:60 to 67:33. In some examples, the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 50:50 to 70:30. In some examples, the immiscible co- continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 50:50 to 67:33. In some examples, the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of 40:60, 50:50, 60:40, or 67:33.

[0019] In some examples, the blending is accomplished using an extruder, such as a twin-screw extruder.

[0020] In some examples, the blending temperature is from 350°C to 400°C, or from 350°C to 390°C, such as 370°C.

[0021] In some examples, the PEEK and PES are blended for an amount of time of from 1 minute to 1 hour, or from 1 minute to 30 minutes, such as 20 minutes.

[0022] In some examples, the PEEK is premixed (e.g., before blending with PES) with a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof. In some examples, the method further comprises blending PEEK and PES together with a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof. In some examples, the method further comprises selecting to include the strengthening additive, the identity of the strengthening additive, the amount of the strengthening additive, or a combination thereof, for example in order to improve the mechanical strength of the porous PEEK scaffold, e.g. to a predetermined value.

[0023] In some examples, the PEEK is premixed (e.g., before blending with PES) with a mineral, such as hydroxyapatite (HA), for example to improve the biocompatibility and / or cell attachment to the porous PEEK scaffold. In some examples, the method further comprises blending PEEK and PES together with a mineral, such as hydroxyapatite (HA), for example to improve the biocompatibility and / or cell attachment to the porous PEEK scaffold.

[0024] In some examples, the annealing comprises quiescent annealing.

[0025] In some examples, the annealing temperature is from 340°C to 400°C, or from 350°C to 390°C, such as from 360°C to 370°C.

[0026] In some examples, the annealing temperature varies across a dimension, such that the immiscible blend is annealed using an annealing temperature gradient. In some examples, the annealing temperature gradient comprises a radial gradient, a linear gradient, a stepped gradient, an exponential gradient, a logarithmic gradient, or a combination thereof.

[0027] In some examples, the immiscible blend is annealed for an amount of time of 1 minute to 12 hours, such as from 1 minute to 6 hours. In some examples, the immiscible blend is annealed for an amount of time of from 15 minutes to 180 minutes, such as from 90 minutes to 180 minutes.

[0028] In some examples, the immiscible blend is annealed for an amount of time of from 90 minutes to 180 minutes and the annealing temperature is from 360°C to 370°C.

[0029] In some examples, the annealing conditions (e.g., time and / or temperature) are selected to control the porosity, the average pore size, or a combination thereof.

[0030] In some examples, the method further comprises, before saturating with a gas, quenching the annealed composition, thereby forming a quenched composition, and then saturating the quenched composition with a gas to form the gas saturated composition. In some examples, quenching the annealed composition comprises submersing the annealed composition in a bath having a temperature of from 0°C to 30°C (e.g., from 0°C to 15°C) for an amount of time of from 1 second to 30 seconds.

[0031] In some examples, saturating the quenched composition or the annealed composition with a gas comprises placing the quenched composition or the annealed composition in a high pressure vessel and exposing the quenched composition or the annealed composition to CO2 (such as supercritical CO2) at a pressure of from 5 to 20 MPa for an amount of time of from 24 hours to 120 hours. In some examples, the amount of time is from 60 hours to 84 hours, such as 72 hours.

[0032] In some examples, saturating the quenched composition or the annealed composition with a gas comprises placing the quenched composition or the annealed composition in a high pressure vessel and exposing the quenched composition or the annealed composition to CO2 (such as supercritical CO2) at a pressure of from 5 to 20 MPa for an amount of time such that the composition has an equilibrium gas concentration for 24 hours.

[0033] In some examples, the gas saturation is performed at a temperature of 35°C.

[0034] In some examples, solid state foaming comprises placing the gas saturated composition in a bath having a temperature of from 200°C to 350°C, from 300°C to 350°C, or from 330°C to 340°C. In some examples, the bath comprises a molten salt mixture. In some examples, the gas saturated composition is placed in the bath for an amount of time of from 1 second to 30 seconds. In some examples, the gas saturated composition is placed in the bath for an amount of time of from 1 second to 15 seconds, such as 7 seconds.

[0035] In some examples, the foamed PES phase comprises from 90-100% of the PES (e.g., from 90-100% of the PES is foamed).

[0036] In some examples, exposing the foamed composition to the solvent comprises submersing the foamed composition in the solvent. In some examples, the solvent comprises N- Methyl-2-Pyrrolidine (NMP). In some examples, the foamed composition is exposed to the solvent for an amount of time of from 4 to 26 hours, or from 12 hours to 36 hours, such as 24 hours.

[0037] In some examples, leaching removes 90-100% of the foamed PES.

[0038] In some examples, the porous PEEK scaffold is substantially free of PES.

[0039] In some examples, after leaching, the porous PEEK scaffold is rinsed and dried. In some examples, the porous PEEK scaffold is rinsed by submersing the porous PEEK scaffold in water (e.g., at 75°C) for an amount of time (e.g., 24 hours) to fully remove the solvent. In some examples, drying comprises baking in an oven (e.g., at 120°C for 8 hours) to remove moisture.

[0040] In some examples, after leaching and / or drying, the method further comprises posttreating the porous PEEK scaffold, for example to improve a property of the porous PEEK scaffold.

[0041] In some examples, after blending and before annealing, the method further comprises extruding the immiscible blend into a filament (e.g., a filament comprising the immiscible blend). In some examples, after forming the filament and before annealing, the method further comprises using the filament for 3D printing, for example for form a 3D printed implant comprising the immiscible blend.

[0042] Additional advantages of the disclosed devices, systems, and methods will be set forth in part in the description which follows, and in part will be obvious from the description. The advantages of the disclosed devices, systems, and methods will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosed devices, systems, and methods, as claimed.

[0043] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0044] BRIEF DESCRIPTION OF THE FIGURES

[0045] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects of the disclosure, and together with the description, serve to explain the principles of the disclosure.

[0046] Figure 1. A schematic of the fabrication process.

[0047] Figure 2A. Cross-section of 50 / 50 PEEK / PES blend before leaching.

[0048] Figure 2B. Cross-section of the 50 / 50 PEEK / PES blend from Figure 2A after leaching.

[0049] Figure 3. DSC results for different PEEK and PES samples.

[0050] Figure 4. Gas concentration result of PEEK / PES blends.

[0051] Figure 5A. Sold-state foaming of neat PEEK. Scale bar is 200 um.

[0052] Figure 5B. Sold-state foaming of 30% PES / 70% PEEK sample. Scale bar is 200 um.

[0053] Figure 5C. Sold-state foaming of 40% PES / 60% PEEK sample. Scale bar is 200 um.

[0054] Figure 5D. Sold-state foaming of 50% PES / 50% PEEK sample. Scale bar is 200 um. Figure 5E. Sold-state foaming of 60% PES / 40% PEEK sample. Scale bar is 200 um. Figure 5F. Sold-state foaming of 67% PES / 33% PEEK sample. Scale bar is 200 um. Figure 6A. Porous PEEK structure after PES extraction: foamed 30% PES / 70% PEEK sample. Scale bar is 200 um.

[0055] Figure 6B. Porous PEEK structure after PES extraction: foamed 40% PES / 60% PEEK sample. Scale bar is 200 um.

[0056] Figure 6C. Porous PEEK structure after PES extraction: foamed 50% PES / 50% PEEK sample. Scale bar is 200 um. Figure 6D. Porous PEEK structure after PES extraction: foamed 60% PES / 40% PEEK sample. Scale bar is 200 um.

[0057] Figure 6E. Porous PEEK structure after PES extraction: foamed 67% PES / 33% PEEK sample. Scale bar is 200 um.

[0058] Figure 7. Remaining sample weight after PES extraction.

[0059] Figure 8 A. Porous PEEK structure with annealing time of 0 min. Scale bar is 100 um.

[0060] Figure 8B. Porous PEEK structure with annealing time of 15 min. Scale bar is 100 um.

[0061] Figure 8C. Porous PEEK structure with annealing time of 45 min. Scale bar is 200 um.

[0062] Figure 8D. Porous PEEK structure with annealing time of 90 min. Scale bar is 200 um.

[0063] Figure 8E. Porous PEEK structure with annealing time of 120 min. Scale bar is 200 um.

[0064] Figure 8F. Porous PEEK structure with annealing time of 180 min. Scale bar is 200 um.

[0065] Figure 9A. Porous PEEK structure with annealing temperature of 350°C.

[0066] Figure 9B. Porous PEEK structure with annealing temperature of 370°C.

[0067] Figure 9C. Porous PEEK structure with annealing temperature of 390°C.

[0068] Figure 10A. Pore size vs. annealing time.

[0069] Figure 10B. Pore size vs. annealing temperature.

[0070] Figure 11. Compressive test results of fabricated porous PEEK.

[0071] Figure 12A. Current PEEK implant application.

[0072] Figure 12B. Proposed solid-porous PEEK implant design.

[0073] Figure 13. The proposed fabrication process.

[0074] Figure 14A-Figure 14B. Filaments with different PEEK / PES weight ratios: (Figure 14A) 25 / 75 and (Figure 14B) 50 / 50, filament diameter 1.75 mm.

[0075] Figure 15A-Figure 15B. Effects of bed and chamber temperature, respectively: (Figure 15A) 130 °C and 130 °C; (Figure 15B) 120 °C and 60 °C.

[0076] Figure 16A. Effects of different printing paths: Zig-zag printing path.

[0077] Figure 16B. Effects of different printing paths: Circular printing path.

[0078] Figure 17A-Figure 17B. 3D printed implant sample: (Figure 17A) Before machining and leaching; (Figure 17B) after machining and leaching.

[0079] Figure 18. SEM images of a cross-section of the porous implant

[0080] Figure 19A. Porous PEEK structure with annealing time: 0 min. Scale bar 200 pm.

[0081] Figure 19B. Porous PEEK structure with annealing time: 45 min. Scale bar 200 pm.

[0082] Figure 19C. Porous PEEK structure with annealing time: 120 min. Scale bar 200 pm.

[0083] Figure 20A: Porous PEEK structure with annealing temperature: 350 °C. Scale bar 200 pm. Figure 20B: Porous PEEK structure with annealing temperature: 370 °C. Scale bar 200 pm.

[0084] Figure 20C: Porous PEEK structure with annealing temperature: 390 °C. Scale bar 200 pm.

[0085] Figure 21A. Pore sizes vs. annealing time, all samples annealed at 370 °C

[0086] Figure 21B. Pore size vs. annealing temperature, all samples annealed for 90 min.

[0087] Figure 22. Compressive test results of fabricated implant samples as compared with a porous PEEK sample. The porosity of the porous PEEK region of the implant is also 50%.

[0088] DETAILED DESCRIPTION

[0089] The devices, methods, and systems described herein may be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples included therein.

[0090] Before the present devices, methods, and systems are disclosed and described, it is to be understood that the aspects described below are not limited to specific synthetic methods or specific reagents, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0091] Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.

[0092] General Definitions

[0093] In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings.

[0094] Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps. As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of’ and “consisting essentially of.”

[0095] As used in the description and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “an agent” includes mixtures of two or more such agents, reference to “the component” includes mixtures of two or more such components, and the like.

[0096] “Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0097] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. By “about” is meant within 5% of the value, e.g., within 4, 3, 2, or 1% of the value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0098] Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, a description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, 6 and any whole and partial increments therebetween. This applies regardless of the breadth of the range.

[0099] When the specific values are disclosed between two end values, it is understood that these end values can also be included.

[0100] For the terms “for example” and “such as,” and grammatical equivalences thereof, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise. It is further understood that these phrases are not used in a restrictive sense, but for explanatory purposes. “Exemplary” means “an example of’ and is not intended to convey an indication of a preferred or ideal embodiment.

[0101] It is understood that throughout this specification the identifiers “first” and “second” are used solely to aid in distinguishing the various components and steps of the disclosed subject matter. The identifiers “first” and “second” are not intended to imply any particular order, amount, preference, or importance to the components or steps modified by these terms.

[0102] Spatially relative terms, such as "beneath," "below," "lower," "above," "upper,"

[0103] “bottom,” “top,” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, elements described as "below" or "beneath" other elements or features would then be oriented "above" the other elements or features. Thus, the term "below" can encompass both an orientation of above and below. The device may be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein are interpreted accordingly.

[0104] It will be understood that when an element is referred to as being "connected" or "coupled" to another element, it can be directly connected or coupled to the other element, or intervening elements may be present. In contrast, when an element is referred to as being "directly connected" or "directly coupled" to another element, there are no intervening elements present. Other words used to describe the relationship between elements or layers should be interpreted in a like fashion (e.g., "between" versus "directly between," "adjacent" versus "directly adjacent," "on" versus "directly on").

[0105] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0106] As used herein, the term "substantially" means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance generally, typically, or approximately occurs.

[0107] Still further, the term “substantially” can, in some aspects, refer to at least about 80 %, at least about 85 %, at least about 90 %, at least about 91 %, at least about 92 %, at least about 93 %, at least about 94 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, or about 100 % of the stated property, component, composition, or other condition for which substantially is used to characterize or otherwise quantify an amount.

[0108] In other aspects, as used herein, the term “substantially free,” when used in the context of a composition or component of a composition that is substantially absent, is intended to refer to an amount that is then about 1 % by weight, e.g., less than about 0.5 % by weight, less than about 0.1 % by weight, less than about 0.05 % by weight, or less than about 0.01 % by weight of the stated material, based on the total weight of the composition.

[0109] The expressions “ambient temperature” and “room temperature” as used herein are understood in the art and refer generally to a temperature from about 20°C to about 35°C. References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a mixture containing 2 parts by weight of component X and 5 parts by weight of component Y, components X and Y are present at a weight ratio of 2:5 and are present in such a ratio regardless of whether additional components are contained in the mixture.

[0110] A weight percent (wt.%) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0111] It is understood that the term “salt,” as used herein, refers to a chemical compound that can be formed form a reaction between an acid and a base. It is understood that the term “salt,” as used herein, encompasses both inorganic and organic salts capable of providing the desired properties to the composition. In still further aspects, a cation of the disclosed herein salts is a metal cation.

[0112] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of ordinary skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to the arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0113] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0114] “Phase,” as used herein, generally refers to a region of a material having a substantially uniform composition which is a distinct and physically separate portion of a heterogeneous system. The term “phase” does not imply that the material making up a phase is a chemically pure substance, but merely that the chemical and / or physical properties of the material making up the phase are essentially uniform throughout the material, and that these chemical and / or physical properties differ significantly from the chemical and / or physical properties of another phase within the material. Examples of physical properties include density, thickness, aspect ratio, specific surface area, porosity, and dimensionality. Examples of chemical properties include chemical composition.

[0115] By “continuous” it is meant a phase such that all points within the phase are directly connected, so that for any two points within a continuous phase there exists a path which connects the two points and does not leave the phase.

[0116] A “bicontinuous” material contains two separate continuous phases such that each phase is continuous, and in which the two phases are interpenetrating. It is impossible to separate the two structures without tearing one of the structures.

[0117] The term “(co)polymer” includes homopolymers, copolymers, or mixtures thereof.

[0118] The term “(meth)acryl. . .” includes “acryl. . “methacryl. . or mixtures thereof.

[0119] As used herein, “molecular weight” refers to number-average molecular weight as measured byJH NMR spectroscopy, unless clearly indicated otherwise.

[0120] Porous Polyether-Ether-Ketone (PEEK) Scaffolds

[0121] Disclosed herein are porous polyether-ether-ketone (PEEK) scaffolds comprising a continuous polyether-ether-ketone (PEEK) phase permeated by a continuous pore phase. In some examples, the polyether-ether-ketone phase and the pore phase can be bicontinuous.

[0122] The continuous pore phase comprises a plurality of pores.

[0123] The plurality of pores can have any shape, such as, for example, a cylinder, a hemicylinder, an elliptical cylinder, a hemi-elliptical cylinder, a cone, a semicone, etc. In some examples, the plurality of pores have a concave shape.

[0124] The plurality of pores can have an average pore size. As used herein “pore size” refers to the largest cross-sectional dimension of a pore in a plane perpendicular to the longitudinal axis of the pore. For example, in the case of a substantially cylindrical pore, the pore size would be the diameter of the pore. In some examples, the average pore size can be substantially the same for the entire length of the pore. In some examples, the average pore size can vary along the length of the pore, (e.g., tapered or conical pores). The average pore size can be determined, for example, using electron microscopy (e.g., scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM)), Brunauer-Emmett-Teller (BET) measurements, porosimetry, or a combination thereof.

[0125] For example, the plurality of pores having an average pore size of 1 micrometer (microns, pm) or more (e.g., 2 pm or more, 3 pm or more, 4 pm or more, 5 pm or more, 6 pm or more, 7 pm or more, 8 pm or more, 9 pm or more, 10 pm or more, 15 pm or more, 20 pm or more, 25 un or more, 30 m or more, 35 pm or more, 40 pm or more, 45 pm or more, 50 pm or more, 60 pm or more, 70 pm or more, 80 pm or more, 90 pm or more, 100 pm or more, 125 pm or more, 150 pm or more, 175 pm or more, 200 pm or more, 225 pm or more, 250 pm or more, 275 pm or more, 300 pm or more, 325 pm or more, 350 pm or more, 375 pm or more, 400 pm or more, 425 pm or more, 450 pm or more, 475 pm or more, 500 pm or more, 525 pm or more, 550 pm or more, or 575 pm or more). In some examples, the plurality of pores can have an average pore size of 600 micrometers (microns, pm) or less (e.g., 575 pm or less, 550 pm or less, 525 pm or less, 500 pm or less, 475 pm or less, 450 pm or less, 425 pm or less, 400 pm or less, 375 pm or less, 350 pm or less, 325 pm or less, 300 pm or less, 275 pm or less, 250 pm or less, 225 pm or less, 200 pm or less, 175 pm or less, 150 pm or less, 125 pm or less, 100 pm or less, 90 pm or less, 80 pm or less, 70 pm or less, 60 pm or less, 50 pm or less, 45 pm or less, 40 pm or less, 35 pm or less, 30 pm or less, 25 pm or less, 20 pm or less, 15 pm or less, 10 pm or less, 9 pm or less, 8 pm or less, 7 pm or less, 6 pm or less, 5 pm or less, 4 pm or less, 3 pm or less, or 2 pm or less). The average pore size of the plurality of pores can range from any of the minimum values described above to any of the maximum values described above. For example, the plurality of pores can have an average pore size of from 1 to 600 micrometers (microns, pm) (e.g., from 1 to 300 pm, from 300 to 600 pm, from 1 to 200 pm, from 200 to 400 pm, from 400 to 600 pm, from 1 to 500 pm, from 1 to 400 pm, from 1 to 100 pm, from 10 to 600 pm, from 20 to 600 pm, from 50 to 600 pm, from 100 to 600 pm, from 200 to 600 pm, from 500 to 600 pm, from 10 to 550 pm, from 20 to 500 pm, from 100 to 400 pm, or from 100 to 300 pm). In some examples, the plurality of pores have an average pore size of from 10 to 600 micrometers (microns, pm). In some examples, the plurality of pores have an average pore size of from 20 to 500 micrometers (microns, pm). In some examples, the plurality of pores have an average pore size of from 100 to 400 micrometers (microns, pm). In some examples, the plurality of pores have an average pore size of from 100 to 300 micrometers (microns, pm).

[0126] In some examples, the plurality of pores have a concave shape and an average pore size of from 1 to 600 micrometers (microns, pm). In some examples, the plurality of pores have a concave shape and an average pore size of from 10 to 600 micrometers (microns, pm). In some examples, the plurality of pores have a concave shape and an average pore size of from 20 to 500 micrometers (microns, pm). In some examples, the plurality of pores have a concave shape and an average pore size of from 100 to 400 micrometers (microns, pm). In some examples, the plurality of pores have a concave shape and an average pore size of from 100 to 300 micrometers (microns, pm).

[0127] In some examples, the plurality of pores can be substantially monodisperse. “Monodisperse” and “homogeneous size distribution,” as used herein, and generally describe a population of pores where all of the pores are the same or nearly the same size. As used herein, a monodisperse distribution refers to pore distributions in which 80% of the distribution (e.g., 85% of the distribution, 90% of the distribution, or 95% of the distribution) lies within 25% of the average pore size (e.g., within 20% of the average pore size, within 15% of the average pore size, within 10% of the average pore size, or within 5% of the average pore size).

[0128] In some examples, the plurality of pores can comprise: a first population of pores having a first average pore size; and a second population of pores having a second average pore size; wherein the first average pore size and the second average pore size are different. In some examples, the plurality of pores can comprise a mixture of a plurality of populations of pores, wherein each population of pores within the mixture is different with respect to average pore size.

[0129] In some examples, the plurality of pores have an average pore size that varies across a dimension of the porous PEEK scaffold, such that the plurality of pores has an average pore size gradient from an initial average pore size to a final average pore size. In some examples, the average pore size gradient comprises a radial gradient, a linear gradient, a stepped gradient, an exponential gradient, a logarithmic gradient, or a combination thereof.

[0130] In some examples, the porous PEEK scaffold has a porosity of 40% or more (e.g., 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, or 85% or more). In some examples, the porous PEEK scaffold has a porosity of 90% or less (e.g., 85% or less, 80% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, or 45% or less). The porosity of the porous PEEK scaffold can range from any of the minimum values described above to any of the maximum values described above. For example, the porous PEEK scaffold can have a porosity of from 40% to 90% (e.g., from 40% to 65%, from 65% to 90%, from 40% to 50%, from 50% to 60%, from 60% to 70%, from 70% to 80%, from 80% to 90%, from 40% to 80%, from 40% to 70%, from 40% to 65%, from 40% to 60%, from 40% to 55%, from 45% to 90%, from 50% to 90%, 55% to 90%, from

[0131] 60% to 90%, from 65% to 90%, from 70% to 90%, from 45% to 85%, from 50% to 80%, or from 50% to 70%). In some examples, the porous PEEK scaffold has a porosity of from 40% to 70%. In some examples, the porous PEEK scaffold has a porosity of from 40% to 65%. In some examples, the porous PEEK scaffold has a porosity of from 50% to 70%. The porosity can be determined, for example, using electron microscopy (e.g., scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM)), Brunauer-Emmett-Teller (BET) measurements, porosimetry, or a combination thereof. In some examples, the plurality of pores have a concave shape and the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70%.

[0132] In some examples, the plurality of pores have an average pore size of from 10 to 600 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70%. In some examples, the plurality of pores have an average pore size of from 20 to 500 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70%. In some examples, the plurality of pores have an average pore size of from 100 to 400 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70%. In some examples, the plurality of pores have an average pore size of from 100 to 300 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70%.

[0133] In some examples, the plurality of pores have a concave shape and an average pore size of from 1 to 600 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70%. In some examples, the plurality of pores have a concave shape and an average pore size of from 10 to 600 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70%. In some examples, the plurality of pores have a concave shape and an average pore size of from 20 to 500 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70%. In some examples, the plurality of pores have a concave shape and an average pore size of from 100 to 400 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70%. In some examples, the plurality of pores have a concave shape and an average pore size of from 100 to 300 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70%.

[0134] In some examples, the porous PEEK scaffold has a compressive strength of 1 MPa or more (e.g., 2 MPa or more, 3 MPa or more, 4 MPa or more, 5 MPa or more, 6 MPa or more, 7 MPa or more, 8 MPa or more, 9 MPa or more, 10 MPa or more, 11 MPa or more, 12 MPa or more, 13 MPa or more, 14 MPa or more, 15 MPa or more, 16 MPa or more, 17 MPa or more, 18 MPa or more, 19 MPa or more, 20 MPa or more, 21 MPa or more, 22 MPa or more, 23 MPa or more, 24 MPa or more, 25 MPa or more, 26 MPa or more, 27 MPa or more, 28 MPa or more, or 29 MPa or more). In some examples, the porous PEEK scaffold has a compressive strength of 30 MPa or less (e.g., 29 MPa or less, 28 MPa or less, 27 MPa or less, 26 MPa or less, 25 MPa or less, 24 MPa or less, 23 MPa or less, 22 MPa or less, 21 MPa or less, 20 MPa or less, 19 MPa or less, 18 MPa or less, 17 MPa or less, 16 MPa or less, 15 MPa or less, 14 MPa or less, 13 MPa or less, 12 MPa or less, 11 MPa or less, 10 MPa or less, 9 MPa or less, 8 MPa or less, 7 MPa or less, 6 MPa or less, 5 MPa or less, 4 MPa or less, 3 MPa or less, or 2 MPa or less). The compressive strength of the porous PEEK scaffold can range from any of the minimum values described above to any of the maximum values described above. For example, the porous PEEK scaffold can have a compressive strength of from 1 to 30 MPa (e.g., from 1 to 15 MPa, from 15 to 30 MPa, from 1 to 10 MPa, from 10 to 20 MPa, from 20 to 30 MPa, from 5 to 30 MPa, from 10 to 30 MPa, from 2 to 28 MPa, or from 8 to 26 MPa). In some examples, the porous PEEK scaffold has a compressive strength of from 8 to 26 MPa. Compressive strength can be measured using methods known in the art, such as using a universal mechanical tester (e.g., an Instron 5980). As used herein, compressive strength is measured using an Instron 5980 universal mechanical tester on the 3 mm x 5 mm surface of a prism sample, with a constant strain rate of 0.5 mm / min and a preload of 10 N.

[0135] In some examples, the porous PEEK scaffold has a compressive modulus of 50 MPa or more (e.g., 55 MPa or more, 60 MPa or more, 65 MPa or more, 70 MPa or more, 75 MPa or more, 80 MPa or more, 85 MPa or more, 90 MPa or more, 95 MPa or more, 100 MPa or more, 105 MPa or more, 110 MPa or more, 115 MPa or more, 120 MPa or more, 125 MPa or more, 130 MPa or more, 135 MPa or more, 140 MPa or more, or 145 MPa or more). In some examples, the porous PEEK scaffold can have a compressive modulus of 150 MPa or less (e.g., 145 MPa or less, 140 MPa or less, 135 MPa or less, 130 MPa or less, 125 MPa or less, 120 MPa or less, 115 MPa or less, 110 MPa or less, 105 MPa or less, 100 MPa or less, 95 MPa or less, 90 MPa or less, 85 MPa or less, 80 MPa or less, 75 MPa or less, 70 MPa or less, 65 MPa or less, 60 MPa or less, or 55 MPa or less). The compressive modulus of the porous PEEK scaffold can range from any of the minimum values described above to any of the maximum values described above. For example, the porous PEEK scaffold can have a compressive modulus of from 50 to 150 MPa (e.g., from 50 to 100 MPa, from 100 to 150 MPa, from 50 to 75 MPa, from 75 to 100 MPa, from 100 to 125 MPa, from 125 to 150 MPa, from 75 to 150 MPa, from 50 to 125 MPa, or from 75 to 125 MPa). Compressive modulus can be measured using methods known in the art, such as using a universal mechanical tester (e.g., an Instron 5980). As used herein, compressive modulus is measured using an Instron 5980 universal mechanical tester on the 3 mm x 5 mm surface of a prism sample, with a constant strain rate of 0.5 mm / min and a preload of 10 N. In some examples, the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa, such as from 8 to 26 MPa, and a compressive modulus of from 50 to 150 MPa.

[0136] In some examples, the plurality of pores have a concave shape and the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa, such as from 8 to 26 MPa, and a compressive modulus of from 50 to 150 MPa.

[0137] In some examples, the plurality of pores have an average pore size of from 10 to 600 micrometers (microns, pm) and the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa, such as from 8 to 26 MPa, and a compressive modulus of from 50 to 150 MPa. In some examples, the plurality of pores have an average pore size of from 20 to 500 micrometers (microns, pm) and the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa, such as from 8 to 26 MPa, and a compressive modulus of from 50 to 150 MPa. In some examples, the plurality of pores have an average pore size of from 100 to 400 micrometers (microns, pm) and the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa, such as from 8 to 26 MPa, and a compressive modulus of from 50 to 150 MPa. In some examples, the plurality of pores have an average pore size of from 100 to 300 micrometers (microns, pm) and the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa, such as from 8 to 26 MPa, and a compressive modulus of from 50 to 150 MPa.

[0138] In some examples, the porous PEEK scaffold has a porosity of from 40% to 90%, from 40% to 70%, from 40% to 65%, or from 50% to 70% and the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa, such as from 8 to 26 MPa, and a compressive modulus of from 50 to 150 MPa.

[0139] In some examples, the plurality of pores have an average pore size of from 10 to 600 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90% (e.g., from 40% to 70%, from 40% to 65%, or from 50% to 70%), a compressive strength of from 1 to 30 MPa (e.g., from 8 to 26 MPa), and a compressive modulus of from 50 to 150 MPa. In some examples, the plurality of pores have an average pore size of from 20 to 500 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90% (e.g., from 40% to 70%, from 40% to 65%, or from 50% to 70%), a compressive strength of from 1 to 30 MPa (e.g., from 8 to 26 MPa), and a compressive modulus of from 50 to 150 MPa. In some examples, the plurality of pores have an average pore size of from 100 to 400 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90% (e.g., from 40% to 70%, from 40% to 65%, or from 50% to 70%), a compressive strength of from 1 to 30 MPa (e.g., from 8 to 26 MPa), and a compressive modulus of from 50 to 150 MPa. In some examples, the plurality of pores have an average pore size of from 100 to 300 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90% (e.g., from 40% to 70%, from 40% to 65%, or from 50% to 70%), a compressive strength of from 1 to 30 MPa (e.g., from 8 to 26 MPa), and a compressive modulus of from 50 to 150 MPa.

[0140] In some examples, the plurality of pores have a concave shape and an average pore size of from 1 to 600 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90% (e.g., from 40% to 70%, from 40% to 65%, or from 50% to 70%), a compressive strength of from 1 to 30 MPa (e.g., from 8 to 26 MPa), and a compressive modulus of from 50 to 150 MPa. In some examples, the plurality of pores have a concave shape and an average pore size of from 10 to 600 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90% (e.g., from 40% to 70%, from 40% to 65%, or from 50% to 70%), a compressive strength of from 1 to 30 MPa (e.g., from 8 to 26 MPa), and a compressive modulus of from 50 to 150 MPa. In some examples, the plurality of pores have a concave shape and an average pore size of from 20 to 500 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90% (e.g., from 40% to 70%, from 40% to 65%, or from 50% to 70%), a compressive strength of from 1 to 30 MPa (e.g., from 8 to 26 MPa), and a compressive modulus of from 50 to 150 MPa. In some examples, the plurality of pores have a concave shape and an average pore size of from 100 to 400 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90% (e.g., from 40% to 70%, from 40% to 65%, or from 50% to 70%), a compressive strength of from 1 to 30 MPa (e.g., from 8 to 26 MPa), and a compressive modulus of from 50 to 150 MPa. In some examples, the plurality of pores have a concave shape and an average pore size of from 100 to 300 micrometers (microns, pm) and the porous PEEK scaffold has a porosity of from 40% to 90% (e.g., from 40% to 70%, from 40% to 65%, or from 50% to 70%), a compressive strength of from 1 to 30 MPa (e.g., from 8 to 26 MPa), and a compressive modulus of from 50 to 150 MPa.

[0141] In some examples, the PEEK implant has a porous region integrated with a solid region, for example, 50% solid and 50% porous region. The porous region has an average pore size from 10 to 500 micrometers. The integral solid and porous implants have a compressive strength in the range of 32-40 MPa and compressive modulus of 620-700 MPa.

[0142] In some examples, the porous PEEK scaffold is biocompatible, biomimetic, or a combination thereof.

[0143] In some examples, the porous PEEK scaffold further comprises a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof. The inclusion of a strengthening additive, the identity of the strengthening additive, the amount of the strengthening additive, or a combination thereof can be selected in order to improve the mechanical strength of the porous PEEK scaffold, for example to a predetermined value.

[0144] In some examples, the porous PEEK scaffold can further include a mineral, such as hydroxyapatite (HA), mixed in the matrix or coated on the inner surface of the pores, for example to improve biocompatibility and / or cell attachment.

[0145] Methods of Making

[0146] Also disclosed herein are methods of making porous polyether-ether-ketone (PEEK) scaffolds, for example any of the porous polyether-ether-ketone (PEEK) scaffolds described herein.

[0147] Blending

[0148] The methods comprise blending polyether-ether-ketone (PEEK) and polyether sulfone (PES) together at a blending temperature to form an immiscible co-continuous blend comprising PEEK and PES. The blending can be accomplished using any suitable means, such as those known in the art, for example any hot polymer mixing equipment known in the art. In some examples, the blending is accomplished using an extruder, such as a twin-screw extruder. In some examples, the blending is accomplished using a Brabender mixer.

[0149] In some examples, the blending temperature is 350°C or more (e.g., 355°C or more, 360°C or more, 365°C or more, 370°C or more, 375°C or more, 380°C or more, 385°C or more, 390°C or more, or 395°C or more). In some examples, the blending temperature is 400°C or less (e.g., 395°C or less, 390°C or less, 385°C or less, 380°C or less, 375°C or less, 370°C or less, 365°C or less, 360°C or less, or 355°C or less). The blending temperature can range from any of the minimum values described above to any of the maximum values described above. For example, the blending temperature can be from 350°C to 400°C (e.g., from 350°C to 375°C, from 375°C to 400°C, from 350°C to 360°C, from 360°C to 370°C, from 370°C to 380°C, from 380°C to 390°C, from 390°C to 400°C, from 350°C to 390°C, from 350°C to 380°C, from

[0150] 350°C to 370°C, from 360°C to 400°C, from 370°C to 400°C, from 380°C to 400°C, from

[0151] 355°C to 395°C, from 360°C to 390°C, from 360°C to 380°C, or from 365°C to 375°C). In some examples, the blending temperature can be from 350°C to 390°C. In some examples, the blending temperature can be 370°C.

[0152] In some examples, the PEEK and PES are blended for an amount of time of 1 minute or more (e.g., 2 minutes or more, 3 minutes or more, 4 minutes or more, 5 minutes or more, 10 minutes or more, 15 minutes or more, 20 minutes or more, 25 minutes or more, 30 minutes or more, 35 minutes or more, 40 minutes or more, 45 minutes or more, 50 minutes or more, or 55 minutes or more). In some examples, the PEEK and PES are blended for an amount of time of 1 hour or less (e.g., 55 minutes or less, 50 minutes or less, 45 minutes or less, 40 minutes or less, 35 minutes or less, 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less). The amount of time that the PEEK and PES are blended can range from any of the minimum values described above to any of the maximum values described above. For example, the PEEK and PES can be blended for an amount of time of from 1 minute to 1 hour (e.g., from 1 to 30 minutes, from 30 to 60 minutes, from 1 to 20 minutes, from 20 to 40 minutes, from 40 to 60 minutes, from 1 to 50 minutes, from 1 to 40 minutes, from 1 to 10 minutes, from 5 to 60 minutes, from 10 to 60 minutes, from 20 to 60 minutes, from 50 to 60 minutes, from 5 to 50 minutes, or from 10 to 40 minutes). In some examples, the PEEK and PES are blended for an amount of time of from 1 minute to 30 minutes. In some examples, the PEEK and PES are blended for an amount of time of 20 minutes.

[0153] In some examples, the blending temperature is from 350°C to 400°C (e.g., from 350°C to 390°C, such as 370°C) and the PEEK and PES are blended for an amount of time of from 1 minute to 1 hour (e.g., from 1 minute to 30 minutes, such as 20 minutes).

[0154] In some examples, the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of 30:70 or more (e.g., 31 :69 or more, 32:68 or more, 33:67 or more, 34:66 or more, 35:65 or more, 36:64 or more, 37:63 or more, 38:62 or more, 39:61 or more,

[0155] 40:60 or more, 41 :59 or more, 42:58 or more, 43:57 or more, 44:56 or more, 45:55 or more,

[0156] 46:54 or more, 47:53 or more, 48:52 or more, 49:51 or more, 50:50 or more, 51 :49 or more,

[0157] 52:48 or more, 53:47 or more, 54:46 or more, 55:45 or more, 56:44 or more, 57:43 or more,

[0158] 58:42 or more, 59:41 or more, 60:40 or more, 61 :39 or more, 62:38 or more, 63:37 or more,

[0159] 64:36 or more, 65:35 or more, 66:34 or more, 67:33 or more, 68:32 or more, or 69:31 or more).

[0160] In some examples, the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of 70:30 or less (e.g., 69:31 or less, 68:32 or less, 67:33 or less, 66:34 or less, 65:35 or less, 64:36 or less, 63:37 or less, 62:38 or less, 61 :39 or less, 60:40 or less, 59:41 or less, 58:42 or less, 57:43 or less, 56:44 or less, 55:45 or less, 54:46 or less, 53:47 or less, 52:48 or less, 51 :49 or less, 50:50 or less, 49:51 or less, 48:52 or less, 47:53 or less, 46:54 or less, 45:55 or less, 44:56 or less, 43:57 or less, 42:58 or less, 41 :59 or less, 40:60 or less, 39:61 or less, 38:62 or less, 37:63 or less, 36:64 or less, 35:65 or less, 34:66 or less, 33:67 or less, 32:68 or less, or 31 :69 or less). The weight ratio of PES:PEEK can range from any of the minimum values described above to any of the maximum values described above. For example, the immiscible co-continuous blend can comprise PES and PEEK in a weight ratio (PES:PEEK) of from 30:70 to 70:30 (e.g., from 30:70 to 50:50, from 50:50 to 70:30, from 30:70 to 40:60, from 40:60 to 50:50, from 50:50 to 60:40, from 60:40 to 70:30, from 30:70 to 60:40, from 40:60 to 70:30, from 40:60 to 60:40, from 31 :69 to 69:31, or from 33:67 to 67:33). In some examples, the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 40:60 to 70:30. In some examples, the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 40:60 to 67:33. In some examples, the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 50:50 to 70:30. In some examples, the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 50:50 to 67:33. In some examples, the immiscible co- continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of 40:60, 50:50, 60:40, or 67:33.

[0161] In some examples, the blending temperature is from 350°C to 400°C (e.g., from 350°C to 390°C, such as 370°C) and the immiscible co-continuous blend can comprise PES and PEEK in a weight ratio (PES:PEEK) of from 30:70 to 70:30 (e.g., from 40:60 to 70:30, from 40:60 to 67:33, from 50:50 to 70:30, or from 50:50 to 67:33).

[0162] In some examples, the PEEK and PES are blended for an amount of time of from 1 minute to 1 hour (e.g., from 1 minute to 30 minutes, such as 20 minutes) and the immiscible co- continuous blend can comprise PES and PEEK in a weight ratio (PES:PEEK) of from 30:70 to 70:30 (e.g., from 40:60 to 70:30, from 40:60 to 67:33, from 50:50 to 70:30, or from 50:50 to 67:33).

[0163] In some examples, the blending temperature is from 350°C to 400°C (e.g., from 350°C to 390°C, such as 370°C), the PEEK and PES are blended for an amount of time of from 1 minute to 1 hour (e.g., from 1 minute to 30 minutes, such as 20 minutes), and the immiscible co- continuous blend can comprise PES and PEEK in a weight ratio (PES:PEEK) of from 30:70 to 70:30 (e.g., from 40:60 to 70:30, from 40:60 to 67:33, from 50:50 to 70:30, or from 50:50 to 67:33).

[0164] In some examples, the PEEK phase is premixed with a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof. The inclusion of a strengthening additive, the identity of the strengthening additive, the amount of the strengthening additive, or a combination thereof can be selected in order to improve the mechanical strength of the porous PEEK scaffold, for example to a predetermined value. Certain additives (e.g., hydroxyapatite (HA)) can also be pre-mixed with PEEK to improve the biocompatibility of the PEEK scaffold.

[0165] In some examples, the PEEK and PES are blended together with a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof. The inclusion of a strengthening additive, the identity of the strengthening additive, the amount of the strengthening additive, or a combination thereof can be selected in order to improve the mechanical strength of the porous PEEK scaffold, for example to a predetermined value. Certain additives (e.g., hydroxyapatite (HA)) can also be blended with PEEK and PES to improve the biocompatibility of the PEEK scaffold.

[0166] Filament making and 3D printing

[0167] In some examples, the methods further comprise extruding the immiscible blend into a filament. In some examples, the methods can further comprise using the filament for 3D printing, for example to form an implant, such as a custom implant.

[0168] For example, the methods can further comprise making a PEEK / PES composite filament and use it for 3D printing customized shape scaffolds. In some examples, the PEEK / PES composite filament is made by blending PEEK and PES pellets in a twin-screw extruder. Before blending, both PEEK and PES pellets are dried at 150°C for 24 hours. The blending temperature is set at 370°C the screw speed at 25 rpm, and blending time at 20 mins. After extrusion, the PEEK / PES filament is used to print the outer region of a custom designed intervertebral spacer implant using high temperature 3D printer. The inner region of the implant is printed with neat PEEK filament.

[0169] Annealing

[0170] The methods further comprise annealing the immiscible blend at an annealing temperature, thereby forming an annealed composition. In some examples, the annealing comprises quiescent annealing.

[0171] In some examples, the annealing temperature is 340°C or more (e.g., 345°C or more, 350°C or more, 355°C or more, 360°C or more, 365°C or more, 370°C or more, 375°C or more, 380°C or more, 385°C or more, 390°C or more, or 395°C or more). In some examples, the annealing temperature is 400°C or less (e.g., 395°C or less, 390°C or less, 385°C or less, 380°C or less, 375°C or less, 370°C or less, 365°C or less, 360°C or less, 355°C or less, 350°C or less, or 345°C or less). The annealing temperature can range from any of the minimum values described above to any of the maximum values described above. For example, the annealing temperature can be from 340°C to 400°C (e.g., from 340°C to 370°C, from 370°C to 400°C, from 340°C to 360°C, from 360°C to 380°C, from 380°C to 400°C, from 340°C to 390°C, from 340°C to 380°C, from 340°C to 350°C, from 350°C to 400°C, from 360°C to 400°C, from 390°C to 400°C, from 350°C to 390°C, or from 360°C to 370°C). In some examples, the annealing temperature can be from 350°C to 390°C. In some examples, the annealing temperature can be from 360°C to 370°C. In some examples, the annealing temperature varies across a dimension, such that the immiscible blend is annealed using an annealing temperature gradient. In some examples, the annealing temperature gradient comprises a radial gradient, a linear gradient, a stepped gradient, an exponential gradient, a logarithmic gradient, or a combination thereof.

[0172] In some examples, the immiscible blend is annealed for an amount of time of 1 minute or more (e.g., 5 minutes or more, 10 minutes or more, 15 minutes or more, 20 minutes or more, 25 minutes or more, 30 minutes or more, 40 minutes or more, 50 minutes or more, 60 minutes or more, 75 minutes or more, 90 minutes or more, 120 minutes or more, 150 minutes or more, 180 minutes or more, 3.5 hours or more, 4 hours or more, 4.5 hours or more, 5 hours or more, 5.5 hours or more, 6 hours or more, 7 hours or more, 8 hours or more, 9 hours or more, 10 hours or more, or 11 hours or more). In some examples, the immiscible blend is annealed for an amount of time of 12 hours or less (e.g., 11 hours or less, 10 hours or less, 9 hours or less, 8 hours or less, 7 hours or less, 6 hours or less, 5.5 hours or less, 5 hours or less, 4.5 hours or less, 4 hours or less, 3.5 hours or less, 180 minutes or less, 150 minutes or less, 120 minutes or less, 90 minutes or less, 75 minutes or less, 60 minutes or less, 50 minutes or less, 40 minutes or less, 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less). The amount of time that the immiscible blend is annealed can range from any of the minimum values described above to any of the maximum values described above. For example, the immiscible blend can be annealed for an amount of time of from 1 minute to 12 hours (e.g., from 1 minute to 6 hours, from 6 hours to 12 hours, from 1 minute to 4 hours, from 4 hours to 8 hours, from 8 hours to 12 hours, from 1 minute to 10 hours, from 1 minute to 8 hours, from 1 minute to 3 hours, from 1 minute to 2 hours, from 1 minute to 1 hour, from 15 minutes to 12 hours, from 30 minutes to 12 hours, from 1 hour to 12 hours, from 1.5 hours to 12 hours, from 2 hours to 12 hours, from 3 hours to 12 hours, from 4 hours to 12 hours, from 5 minutes to 10 hours, from 10 minutes to 8 hours, from 15 minutes to 6 hours from 15 minutes to 180 minutes, or from 90 minutes to 180 minutes). In some examples, the immiscible blend is annealed for an amount of time of 1 minute to 6 hours. In some examples, the immiscible blend is annealed for an amount of time of from 15 minutes to 180 minutes. In some examples, the immiscible blend is annealed for an amount of time of from 90 minutes to 180 minutes.

[0173] In some examples, the immiscible blend is annealed for an amount of time of from 1 minute to 12 hours and the annealing temperature is from 340°C to 400°C. In some examples, the immiscible blend is annealed for an amount of time of from 90 minutes to 180 minutes and the annealing temperature is from 360°C to 370°C. In some examples, the annealing conditions (e.g., time and / or temperature) are selected to control the porosity, the average pore size, or a combination thereof.

[0174] Quenching

[0175] The methods optionally further comprise quenching the annealed composition, thereby forming a quenched composition. In some examples, quenching the annealed composition comprises submersing the annealed composition in a bath having a temperature of from 0°C to 30°C (e.g., from 0°C to 15°C) for an amount of time of from 1 second to 30 seconds.

[0176] For example, the bath can have a temperature of 0°C or more (e.g., 5°C or more, 10°C or more, 15°C or more, 20°C or more, or 25°C or more). In some examples, the bath can have a temperature of 30°C or less (e.g., 25°C or less, 20°C or less, 15°C or less, 10°C or less, or 5°C or less). The temperature of the bath can range from any of the minimum values described above to any of the maximum values described above. For example, the bath can have a temperature of from 0°C to 30°C (e.g., from 0°C to 15°C, from 15°C to 30°C, from 0°C to 10°C, from 10°C to 20°C, from 20°C to 30°C, from 0°C to 25°C, from 0°C to 20°C, from 5°C to 30°C, from 10°C to 30°C, from 5°C to 25°C, or from 10°C to 20°C). In some examples, the bath can have a temperature of from 0°C to 15°C.

[0177] In some examples, the annealed composition can be submersed in the bath for an amount of time of 1 second or more (e.g., 5 seconds or more, 10 seconds or more, 15 seconds or more, 20 seconds or more, or 25 seconds or more). In some examples, the amount of time can be 30 seconds or less (e.g., 25 seconds or less, 20 seconds or less, 15 seconds or less, 10 seconds or less, or 5 seconds or less). The amount of time the annealed composition is submersed in the bath can range from any of the minimum values described above to any of the maximum values described above. For example, the annealed composition can be submersed in the bath for an amount of time of from 1 second to 30 seconds (e.g., from 1 to 15 seconds, from 15 to 30 seconds, from 1 to 10 seconds, from 10 to 20 seconds, from 20 to 30 seconds, from 1 to 25 seconds, from 1 to 20 seconds, from 5 to 30 seconds, from 10 to 30 seconds, from 5 to 25 seconds, or from 10 to 20 seconds).

[0178] In some examples, quenching the annealed composition comprises submersing the annealed composition in a bath having a temperature of from 0°C to 15°C for an amount of time of from 1 second to 30 seconds.

[0179] Gas Saturation

[0180] The methods further comprise saturating either the annealed composition or the quenched composition with a gas, thereby forming a gas saturated composition. In some examples, saturating the annealed composition or the quenched composition with a gas comprises placing the annealed composition or the quenched composition in a high pressure vessel and exposing the annealed composition or the quenched composition to CO2 (such as supercritical CO2) at a pressure of from 5 to 20 MPa for an amount of time of from 24 hours to 120 hours. In some examples, saturating the annealed composition or the quenched composition with a gas comprises placing the annealed composition or the quenched composition in a high pressure vessel and exposing the annealed composition or the quenched composition to CO2 (such as supercritical CO2) at a pressure of from 5 to 20 MPa for an amount of time such that the composition has an equilibrium gas concentration for 24 hours.

[0181] For example, the pressure can be 5 MPa or more (e.g., 6 MPa or more, 7 MPa or more, 8 MPa or more, 9 MPa or more, 10 MPa or more, 11 MPa or more, 12 MPa or more, 13 MPa or more, 14 MPa or more, 15 MPa or more, 16 MPa or more, 17 MPa or more, 18 MPa or more, or 19 MPa or more). In some examples, the pressure can be 20 MPa or less (e.g., 19 MPa or less, 18 MPa or less, 17 MPa or less, 16 MPa or less, 15 MPa or less, 14 MPa or less, 13 MPa or less, 12 MPa or less, 11 MPa or less, 10 MPa or less, 9 MPa or less, 8 MPa or less, 7 MPa or less, or 6 MPa or less). The pressure can range from any of the minimum values described above to any of the maximum values described above. For example, the pressure can be from 5 to 20 MPa (e.g., from 5 to 12.5 MPa, from 12.5 to 20 MPa, from 5 to 10 MPa, from 10 to 15 MPa, from 15 to 20 MPa, from 5 to 15 MPa, from 10 to 20 MPa, or from 5 to 15 MPa). In some examples, the pressure can be 20 MPa.

[0182] For example, the amount of time can be 24 hours or more (e.g., 30 hours or more, 36 hours or more, 42 hours or more, 48 hours or more, 54 hours or more, 60 hours or more, 66 hours or more, 72 hours or more, 78 hours or more, 84 hours or more, 90 hours or more, 96 hours or more, 102 hours or more, 108 hours or more, or 114 hours or more). In some examples, the amount of time can be 120 hours or less (e.g., 114 hours or less, 108 hours or less, 102 hours or less, 96 hours or less, 90 hours or less, 84 hours or less, 78 hours or less, 72 hours or less, 66 hours or less, 60 hours or less, 54 hours or less, 48 hours or less, 42 hours or less, 36 hours or less, or 30 hours or less). The amount of time can range from any of the minimum values described above to any of the maximum values described above. For example, the amount of time can be from 24 to 120 hours (e.g., from 24 to 72 hours, from 72 to 120 hours, from 24 to 48 hours, from 48 to 72 hours, from 72 to 96 hours, from 96 to 120 hours, from 24 to 96 hours, from 24 to 84 hours, from 24 to 60 hours, from 48 to 120 hours, from 60 to 120 hours, from 84 to 120 hours, from 48 to 96 hours, or from 60 to 84 hours). In some examples, the amount of time is from 60 hours to 84 hours. In some examples, the amount of time is 72 hours. In some examples, the gas saturation is performed at a temperature of 35°C.

[0183] Solid State Foaming

[0184] The methods further comprise solid state foaming the gas saturated composition, thereby forming a foamed composition.

[0185] In some examples, solid state foaming comprises placing the gas saturated composition in a bath having a temperature of from 200°C to 350°C.

[0186] For example, the bath can have a temperature of 200°C or more (e.g., 210°C or more, 220°C or more, 230°C or more, 240°C or more, 250°C or more, 260°C or more, 270°C or more, 280°C or more, 290°C or more, 300°C or more, 310°C or more, 320°C or more, 330°C or more, or 340°C or more). In some examples, the bath can have a temperature of 350°C or less (e.g., 340°C or less, 330°C or less, 320°C or less, 310°C or less, 300°C or less, 290°C or less, 280°C or less, 270°C or less, 260°C or less, 250°C or less, 240°C or less, 230°C or less, 220°C or less, or 210°C or less). The temperature of the bath can range from any of the minimum values described above to any of the maximum values described above. For example, the bath can have a temperature of from 200°C to 350°C (e.g., from 200°C to 275°C, from 275°C to 350°C, from 200°C to 250°C, from 250°C to 300°C, from 200°C to 350°C, from 300°C to 350°C, from 200°C to 340°C, from 200°C to 330°C, from 200°C to 320°C, from 200°C to 310°C, from 200°C to 300°C, from 200°C to 275°C, from 225°C to 350°C, from 250°C to 350°C, from 275°C to 350°C, from 300°C to 350°C, from 310°C to 350°C, from 320°C to 350°C, from 330°C to 350°C, from 225°C to 340°C, from 300°C to 340°C, or from 330°C to 340°C). In some examples, solid state foaming comprises placing the gas saturated composition in a bath having a temperature of from 300°C to 350°C. In some examples, solid state foaming comprises placing the gas saturated composition in a bath having a temperature of from 330°C to 340°C.

[0187] In some examples, the bath comprises a molten salt mixture.

[0188] In some examples, the gas saturated composition is placed in the bath for an amount of time of from 1 second to 30 seconds.

[0189] In some examples, the gas saturated composition is placed in the bath for an amount of time of 1 second or more (e.g., 5 seconds or more, 10 seconds or more, 15 seconds or more, 20 seconds or more, or 25 seconds or more). In some examples, the amount of time can be 30 seconds or less (e.g., 25 seconds or less, 20 seconds or less, 15 seconds or less, 10 seconds or less, or 5 seconds or less). The amount of time the gas saturated composition is placed in the bath can range from any of the minimum values described above to any of the maximum values described above. For example, the gas saturated composition is placed in the bath for an amount of time of from 1 second to 30 seconds (e.g., from 1 to 15 seconds, from 15 to 30 seconds, from 1 to 10 seconds, from 10 to 20 seconds, from 20 to 30 seconds, from 1 to 25 seconds, from 1 to 20 seconds, from 5 to 30 seconds, from 10 to 30 seconds, from 5 to 25 seconds, or from 10 to 20 seconds). In some examples, the gas saturated composition is placed in the bath for an amount of time of from 1 second to 15 seconds. In some examples, the gas saturated composition is placed in the bath for 7 seconds.

[0190] In some examples, solid state foaming comprises placing the gas saturated composition in a bath having a temperature of from 200°C to 350°C (e.g., from 300°C to 350°C or from 330°C to 340°C) for an amount of time of from 1 to 30 seconds (e.g., from 1 to 15 seconds, such as 7 seconds).

[0191] The foamed composition comprises a foamed PES phase and a substantially unfoamed PEEK phase. In some examples, the foamed PES phase comprises from 90-100% of the PES (e.g., from 90-100% of the PES is foamed). For example, 90% or more of the PES is foamed (e.g., 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more). In some examples, substantially all of the PES is foamed.

[0192] Leaching

[0193] The methods further comprise exposing the foamed composition to a solvent thereby leaching the foamed PES phase to form the porous PEEK scaffold. In some examples, exposing the foamed composition to the solvent comprises submersing the foamed composition in the solvent. The solvent can comprise any solvent that preferentially dissolves PES over PEEK, such as any solvent that dissolves PES by does not dissolve PEEK. In some examples, the solvent comprises DCM (Dichloromethane). In some examples, the solvent comprises N-Methyl-2- Pyrrolidine (NMP).

[0194] In some examples, the foamed composition is exposed to the solvent for an amount of time of 4 hours or more (e.g., 6 hours or more, 8 hours or more, 10 hours or more, 12 hours or more, 14 hours or more, 16 hours or more, 18 hours or more, 20 hours or more, 22 hours or more, 24 hours or more, 26 hours or more, 28 hours or more, 30 hours or more, 32 hours or more, or 34 hours or more). In some examples, the foamed composition is exposed to the solvent for an amount of time of 36 hours or less (e.g., 34 hours or less, 32 hours or less, 30 hours or less, 28 hours or less, 26 hours or less, 24 hours or less, 22 hours or less, 20 hours or less, 18 hours or less, 16 hours or less, 14 hours or less, 12 hours or less, 10 hours or less, 8 hours or less, or 6 hours or less). The amount of time the foamed composition is exposed to the solvent can range from any of the minimum values described above to any of the maximum values described above. For example, the foamed composition can be exposed to the solvent for an amount of time of from 4 hours to 36 hours (e.g., from 4 to 20 hours, from 20 to 36 hours, from 4 to 12 hours, from 12 to 20 hours, from 20 to 28 hours, from 28 to 36 hours, from 4 to 32 hours, from 4 to 28 hours, from 4 to 24 hours, from 4 to 16 hours, from 4 to 8 hours, from 8 to 36 hours, from 12 to 36 hours, from 16 to 36 hours, from 24 to 36 hours, from 8 to 32 hours, or from 12 to 28 hours). In some examples, the foamed composition is exposed to the solvent for an amount of time of from 12 hours to 36 hours. In some examples, the foamed composition is exposed to the solvent for an amount of time of 24 hours.

[0195] In some examples, leaching removes 90-100% of the foamed PES. For example, 90% or more of the foamed PES is removed by leaching (e.g., 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more). In some examples, the porous PEEK scaffold is substantially free of PES.

[0196] Rinsing and / or Drying

[0197] In some examples, after leaching, the porous PEEK scaffold is rinsed and dried. In some examples, the porous PEEK scaffold is rinsed by submersing the porous PEEK scaffold in water (e.g., at 75°C) for an amount of time (e.g., 24 hours) to fully remove the solvent. In some examples, drying comprises baking in an oven (e.g., at 120°C for 8 hours) to remove moisture.

[0198] Post- Treatment(s)

[0199] In some examples, after leaching and / or drying, the method further comprises posttreating the porous PEEK scaffold, for example to improve a property of the porous PEEK scaffold, such as strength, cell attachment, etc.

[0200] In some examples, the post-treatment comprises heat treating the porous PEEK scaffold to improve the strength of the porous PEEK scaffold.

[0201] In some examples, the post-treatment comprises coating the porous structure with a mineral such as hydroxyapatite to improve cell attachment to the porous PEEK scaffold.

[0202] Methods of Use

[0203] Also disclosed herein are methods of use of any of the porous PEEK scaffolds described herein. For example, also disclosed herein are methods of use of any of the porous PEEK scaffolds described herein, for example in a system, an article, and / or a device.

[0204] In some examples, the methods can comprise using the porous PEEK scaffold as a tissue engineering scaffold. In some examples, the method comprises using the porous PEEK scaffold as a bone implant, such as a trabecular bone implant. In some examples, the method comprises using the porous PEEK scaffold as a cervical disc spacer or cage. In some examples, the methods can comprise using the porous PEEK scaffold as a filter, as a substrate for biochemical sensing, or a combination thereof.

[0205] Also disclosed herein are articles of manufacture and / or devices comprising any of the porous PEEK scaffolds disclosed herein. For example, the article and / or device can be a tissue engineering scaffold. In some examples, the article or device comprises a bone implant, such as a trabecular bone implant. In some examples, the article or device comprises a cervical disc spacer or cage.

[0206] In some examples, the porous PEEK scaffold can be assembled together with a solid PEEK structure to fabricate an implant, such as a bone implant, for example a cervical disc spacer.

[0207] In some examples, the porous PEEK scaffold can be assembled together with a 3D printed structure, which can be dense or porous, to fabricate a customized implant, such as a bone implant, for example a cervical disc spacer.

[0208] In some examples, the immiscible blend of PEEK and PES can be printed together with neat PEEK to form an integral device, which, after leaching, has dense and porous regions with optimized mechanical and osteointegration properties for customized implants such as a bone implant, for example a cervical disc spacer.

[0209] In some examples, the article or device comprises a filter, a substrate for biochemical sensing, or a combination thereof.

[0210] A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

[0211] The examples below are intended to further illustrate certain aspects of the systems and methods described herein, and are not intended to limit the scope of the claims.

[0212] EXAMPLES

[0213] The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present invention which are apparent to one skilled in the art.

[0214] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of measurement conditions, e.g., component concentrations, temperatures, pressures and other measurement ranges and conditions that can be used to optimize the described process.

[0215] Example 1 - 1 Method to Create Biomimetic Porous Polyether-ether-ketone Scaffolds for Bone Implants

[0216] Abstract. Poly-ether-ether-ketone (PEEK) is a high strength polymer with strong potential for medical use, especially for bone implants. Herein, a method of making biomimetic porous PEEK scaffold is developed by combining annealing of immiscible PEEK / polyethersulfone (PES) blends with solid-state foaming. Mixing PEEK with PES with particular weight ratios generated a co-continuous phase structure. With solid-state foaming, the sacrificial PES phase can be effectively removed by leaching. By annealing the immiscible blend under certain conditions, the pore size and pore gradient can also be controlled. This study reports the process conditions of the proposed PEEK scaffold fabrication process, which yields rapid leaching of PES without significantly affecting the mechanical strength of the porous PEEK structure. It is demonstrated herein that the PEEK scaffolds generated by PES leaching and foaming can achieve fully interconnected pores with controllable pore size (and potentially pore size gradients). The fabrication method described herein enables biomimetic porous PEEK implants that have not been shown before.

[0217] Introduction. In recent years, poly-ether-ether-ketone (PEEK) has become a popular candidate for medical use as implants. Traditionally, for a material to be used as medical implants it needs to be biocompatible, bio attachable, and have proper mechanical properties [1], For certain scaffolds, biodegradability and interconnected porous structure are also required. PEEK is a high temperature-resistant plastic with a high melting point of 343°C. PEEK is thermally stable and biocompatible at the same time [2], Unlike metal implants, PEEK will not create artifacts in medical radiographic evaluation, such as X-ray and CT, which provides good potential for bone implant uses [3], However, the chemical inertness of PEEK greatly reduces the bone bonding force and prevents the formation of connective tissue surrounding the material, because it typically has poor osseointegration and low cell attachment force [4, 5],

[0218] Several methods have been proposed to improve the bioactivity and biocompatibility of PEEK implants, including increasing the surface roughness to improve osteoblast adhesion [6], adding organic / inorganic or mineral phase such as hydroxyapatite or TiCh to improve osseointegration and mechanical properties [7], and generating porous and interconnected pores to improve the in-growth of osteoblasts [8], In tissue engineering applications, interconnected pores are desired since the they provide space for cells to grow, ensure cellular penetration, and allow diffusion of nutrient and waste exchange in and out of the scaffold [9], The porous structure can also improve the bonding force between the bone and the implant because a stronger interlocking interface is formed. However, due to the high melting point and good chemical resistance of PEEK, generating a porous structure with high mechanical properties in PEEK has been a challenging topic in the fields of thermal insulation and medical bone implants

[0219]

[0010] .

[0220] The most used method to generate porous PEEK structures is salt leaching. Evans et al.

[0221]

[0011] fabricated porous PEEK scaffolds by using hot compression of cubic or spherical sodium chloride particles on the top and bottom surfaces of a solid PEEK block. The salt particles were then leached with water. This method has been commercialized for medical use. However, only a thin layer of 1-2 mm on the top and bottom surface has interconnected pores and the pore size is hard to control. Further improvements have been applied to the salt compression methods. Siddiq et al.

[0012] fabricated porous PEEK structures with approximately 85% open porosity using hot compaction of PEEK powder with large spherical salt particles. Conrad et al.

[0013] studied the effects of the salt porogen on the porous PEEK architecture, permeability, and mechanical strength. A thick layer of porous PEEK / hydroxyapatite mixture was built by compression molding and leaching, and achieved porosity range from 75%-90% with average pore sizes around 300-400 um. For salt compression, since the porous structure is highly dependent on the salt particle size, shape, and contact, these methods can only produce porosity of 75% or higher, with limited geometry shape and uniform pores in the range of 300-600 um. A method that can produce both large pores and small pores with pore gradients that mimic the natural bone structure is still needed.

[0222] Solvent casting and particle leaching methods have also been applied to generate porous PEEK structures. Uddin et al. [12, 14] dissolved PEEK in an organic solvent and mixed it with salt particles and hydroxyapatite. The results showed good interconnectivity with large pores around 400 um. However, the organic solvent used to dissolve PEEK is hard to remove.

[0223] Chemical treatments have also been used to improve the PEEK surface roughness and generate porous structures. Wang et al.

[0015] used sulfonation of PEEK surfaces to improve the hydrophilicity and generate porous surface for bone implants. However, the mechanical properties of PEEK were greatly reduced after the sulfonation. Only a thin surface layer of porous structure is generated. Additive manufacturing or 3D printing methods can be used to fabricate arbitrary internal and external geometries for various applications. Several studies have attempted to print porous PEEK using selective laser sintering (SLS). However, due to the imbalanced heating process, sample geometry and mechanical strength were greatly affected

[0016] , Spece et al.

[0017] and Zheng et al.

[0018] printed porous PEEK scaffolds using fused filament fabrication (FFF). Both studies showed that the 3D printed scaffolds benefitted from the interconnected scaffold structure which could improve the biocompatibility and cell attachment force. However, the lattice structure created using FFF has convex PEEK surfaces that are less inducive for cell attachment, and the resolution that current FFF techniques can achieve is about 400-500 um, which is larger than the optimal pore size 100-400 um for bone tissue engineering [19, 20],

[0224] Herein, a method is proposed for fabricating porous PEEK structures by combining annealing of an immiscible polymer blend with solid-state foaming. Heterogeneous polymer blends are non-equilibrium structures because of their large interfacial area. The interfacial tension can cause a reduction of interfacial area in the viscous blends

[0021] , Morphologies obtained after blending will start changing when left in a quiescent fluid state, leading to a coarsening of the phase dimensions

[0022] , Past work has shown that immiscible polymers in a molten state appear to develop a bi-continuous phase structure when mixed with a proper weight ratio, which provides good potential for generating an interconnected pore structure. The evolution of the pore morphology during the annealing process varies depending on the mechanism and the initial polymer morphology. Different mechanisms have different effects on the coarsening process both in terms of the extent and the rate of change of the phase dimensions

[0023] , Some typical mechanisms include coalescence, breakup, retraction, and end-pinching.

[0225] Although literature on the immiscible blends and molten quiescent morphology of PEEK with other polymers is very limited, studies have shown results for immiscible polymers with lower melting temperatures. Several studies have shown the feasibility of generating interconnected porous structures with PL A polymers. Chen et al. produced interconnected PL A scaffold with PLA / PVP blend by annealing the sample in super-critical CO2 and leached PVP with water

[0024] , Zhou et al.

[0038] used immiscible polylactic acid and polystyrene (PLA / PS) and Ma et al.

[0025] mixed PLA with sucrose and generated fully interconnected PLA scaffold without using any organic solvent.

[0226] In addition, several research groups have studied the annealing process and polymer weight ratios on the phase morphology changes. Veenstra et al. observed co-continuous morphology for polystyrene (PS) and poly ether-ester immiscible blends with weight ratios ranging from 30% to 80% and studied the phase breakup and retraction with annealing time

[0026] , Yu et al. studied the annealing behavior of polystyrene (PS) and poly-methyl-methacrylate (PMMA) polymer blend. By considering various interactions such as van der Waals forces, Brownian motion, interfacial tension, and viscous resistance, a physics base model was developed to predict the phase size change based on the annealing conditions

[0027] . Although immiscible polymer mixtures such as PLA / PVP or other low melt temperature polymer mixtures were studied before to fabricate tissue engineering scaffolds

[0024] , PEEK is a high strength and high temperature material that behaves differently from previous polymers. The PEEK based material system represents new challenges and opportunities for fabricating biomimetic porous PEEK structures.

[0227] Experimental

[0228] Experimental Process. PEEK pellets were obtained from Victrex (Grade 450G) and PES pellets were Veradel A301NT. The density of PEEK is 1.3 g / cm3and the density of PES is 1.32 g / cm3. The melting temperature of PEEK is 343°C and the glass transition temperature for PES is around 230°C. The process temperature of PES can be as high as 400°C. The designed production process is shown in Figure 1. PEEK and PES pellets were first mixed using a twin- screw extruder (Thermal Science MiniLab II). Before mixing, both pellets were dried at 150°C for 24 hours. To determine the proper mixing conditions, different weight ratios were tested. The processing temperature while blending was chosen to be 370°C. The screw speed was set to be 25 rpm, and blending time was set at 20 mins. Although the recommended processing temperatures of the two materials are different, both materials remained relatively highly viscous without degradation.

[0229] Quiescent Annealing. After the mixing process, the mixture was annealed in a hot oven to achieve interconnected morphology with different phase sizes. Since immiscible polymer blends are non-equilibrium structures, the interfacial tension between two polymer phases will cause a reduction of interfacial area in the viscous blends. When modeling the break up and coarsening process of the immiscible polymer blends, the system can be treated as a long cylindrical thread of an incompressible, viscous fluid described as Raleigh’s viscous jet. On top of Raleigh’s viscous jet, Tomotika calculated the change of maximally unstable mode with change in viscosity ratio of different fluids. McMaster found that the coarsening effect for immiscible polymer blends with both co-continuous and fibrous morphology can be modeled as break up of long cylinder viscous liquid jet

[0028] ,

[0230] By combining Tomotika's study for viscous jet and McMaster's study, several studies proposed that the driving force for the coarsening process during quiescent annealing was a capillary pressure effect [27-30], The growth rate of pore size dR / dt in the immiscible co- continuous blend should be directly related to dcr / dt: where R is the pore or phase size, t is the annealing time, a is the distortion amplitude of the liquid jet, ao is the original distortion amplitude or initial phase diameter, T]cis the viscosity of the continuous phase, and Q( , p) is the Tomotika function related to the dominant wavelength A and the viscosity ratio p. It is expected that as the annealing time increases, the size of both phases will increase. The exact growth rate is determined by the interfacial tension and the zero shear rate viscosities, which are material dependent.

[0231] Solid State Foaming. After the annealing process, the samples went through the solid- state foaming process using supercritical CO2. The samples were saturated in a high-pressure vessel with supercritical CO2 at 20 MPa and 35°C. The gas concentration of the mixture was recorded every 12-24 hours to study the saturation behavior of the PEEK / PES mixture. When they reached the equilibrium gas concentrations for more than 12 hrs, the samples were taken out from the pressure vessel, and immediately foamed at 340°C.

[0232] Solvent Leaching. Foamed samples were leached in glass vials to remove the PES phase. The solvent used was N-Methyl-2-Pyrrolidine (NMP) since PES is soluble while PEEK has excellent resistance to NMP at room temperature. The foamed PEEK / PES were leached at room temperature (25°C) for 24 hours, and then submersed in hot water (75°C) for 24 hours to fully remove the organic solvent on the sample surface. After cleaning with water, the samples were baked in oven at 120°C for 8 hours to remove moisture. The initial and final weights of the samples were recorded.

[0233] Sample Characterization. The crystallization behavior of PEEK / PES was assessed using differential scanning calorimetry (DSC) in a temperature range from 25 to 400°C with the procedure described in the following section. The crystallinity was calculated by the following formula: where SHmand SHCCare the measured enthalpies of melting and cold crystallization during the DSC scan, respectively, and is the melting enthalpy of 100% crystalline. Since PES is fully amorphous, the enthalpy is only measured for PEEK and the value is set to be 130 J / g according to literature. The morphology of non-foamed, foamed, and leached PEEK / PES blends were observed with a VEGA3 TESCAN scanning electron microscope (SEM). Cross-section surfaces of the samples were prepared by freeze-fracturing with liquid nitrogen, and sputter coating of a thin layer of gold. The software ImageJ was used to measure the pore sizes and pore distribution from the SEM images. Compression tests with a preload of 10 N and a constant strain rate of 0.5 mm / min were conducted using Instron 5980 machine to characterize the mechanical strength of the final porous PEEK samples.

[0234] Results and Discussion

[0235] PEEK / PES Polymer Mixing and Crystallinity. PEEK / PES immiscible blends from the twin extruder were freeze fractured and the cross sections were examined with SEM. Figure 2A shows the cross section of a sample with 50% PEEK and 50% PES by weight. SEM images with mixing ratios ranging from 30% PEEK and 70% PES to 70% PEEK and 30% PES were very similar. Therefore, only one case is shown in the figures. From the images a clear boundary between PEEK and PES phase cannot be observed. The thin white boundaries shown in the images were caused by freeze fracture when preparing the cross-sectional samples. In order to have a clear observation of the two phases, the mixture is submersed in the organic solvent to leach out the PES phase. As shown in Figure 2B, it can be observed that small pores of PES are uniformly distributed across the whole cross section. Thus, it can be concluded that the PEEK and PES are well mixed after extrusion.

[0236] Crystallinity affects both the gas saturation rate and equilibrium gas concentration of a polymer sample. The crystallinity of as-received PES, as-received PEEK, and 50-50 PEEK / PES blend obtained in this study were measured with DSC and the results are shown in Figure 3. Comparing the area of the melting peaks, the crystallinity of as-received PEEK, PES, and 50-50 PEEK / PES are determined to be 30%, 0%, and 18% correspondingly. As-received PES is a fully amorphous polymer without any major melting peaks, while the as-received PEEK is a semicrystalline polymer with a large melting peak around 340°C. There is also a major melting peak around 340°C for the PEEK / PES sample. Based on the crystallinity values, it can be observed that the crystallinity of the sample is reduced when PES is blended into the PEEK mixture.

[0237] PEEK / PES Gas Saturation and Solid-State Foaming Results. The CO2 saturation behavior of PEEK / PES mixtures with different weight ratios was also studied herein. The results are shown Figure 4. For different PEEK / PES blends, the higher the PES content, the faster the CO2 uptake and higher the final equilibrium gas concentration. The equilibrium gas concentration for 70-30, 50-50, and 30-70 PEEK / PES samples was 6.9%, 7.8%, and 10%, respectively, under the saturation pressure of 20 MPa. As a comparison, the gas concentration for as-received PEEK is only 4%, which is much lower than any of the PEEK / PES samples. The PEEK / PES samples also reached the equilibrium gas concentration much faster at about 48-60 hrs., as compared to 120 hrs. for as-received PEEK. This phenomenon is expected as the crystal region of polymer does not absorb any gas, and it impedes gas diffusion to the amorphous region.

[0238] The solid-state foaming behaviors of PEEK / PES blends with a PES weight ratio ranging from 30% to 70% were studied. PEEK has a melting temperature of 343°C, which is higher than the 230°C glass transition temperature of PES. Preliminary studies showed that PEEK barely foamed at 300°C. Thus, the foaming temperature was chosen to be 330°C, and the foaming time was set to be 7 s. Since the annealing conditions for the immiscible blend plays a role in the phase morphology as well, a consistent annealing time of 90 mins and annealing temperature of 360°C were applied to all samples.

[0239] The cross-sections of foamed samples for different weight ratios are shown in Figure 5A - Figure 5F.

[0240] The foaming result of neat PEEK is shown in Figure 5A. Since PEEK is a semicrystalline polymer, the gas absorption is non-uniform, which results in part of the cross-section showing that PEEK foamed with large cells, while other parts did not foam or only foamed with very small cells.

[0241] In the 30% PES sample shown in Figure 5B, PEEK is foamed together with PES. However, foamed PES is only observed in the center of the sample, while large gaps between the PEEK and PES phase exist in the rest of the area. This phenomenon is because the PES phase would foam first in the foaming process, and when the temperature is raised too high for PES, the PES bubbles would collapse. At the same time, PEEK would start to foam. This foaming nonuniformity was caused by the temperature distribution in the sample during the foaming process. Because of its low composition, the PES phase resides in the PEEK matrix as isolated spheres.

[0242] When the PES content is 40% or higher in the mixture, the PEEK and PES phases show a co-continuous morphology (Figure 5C-Figure 5F). From Figure 5C-Figure 5F, it can be observed that small foamed cells exist uniformly in the PES domain of the blended mixture. From Figure 5C, the boundary between PEEK and PES cannot be clearly observed, which is due to the small pore size caused by the short annealing time. For Figure 5D-Figure 5F, a clear boundary between PEEK and PES can be observed, since the PEEK phase is barely foamed, while most of the foaming appears in the PES phase. Although there was no reported result on solid state foaming of PEEK / PES mixtures so far, a similar phenomenon has been observed when foaming the mixture of PEEK and p-PEI by Nemoto et al

[0031] , The results showed that PEEK and the amorphous p-PEI were mixed with a phase size of 0.1 um, and on the micro scale only PEI phase was foamed. This phenomenon is due to the fact that PEEK is semi-crystalline polymer and contains a portion of crystal part. Even if a fast cooling process is applied to the samples, there is still some crystallinity remaining in the sample. Since CO2 dissolves only in the amorphous phase, as the PES content increases, the CO2 is much more likely to dissolve in the PES phase instead of the PEEK phase. Thus, as the PES ratio increased, the crystalline phase associated with PEEK became less prevalent, and nucleation would occur in PES phase first.

[0243] Continuity and Phase Retraction. The continuity and phase morphology for different PES wt% was also studied. The PEEK / PES mixture with PES wt% from 30% to 67% was annealed for 90 mins and under temperature 360°C. Then the samples were saturated in sc-CCh at 20 MPa for 72 hrs and foamed in a hot bath at 330°C. After solid state foaming, the samples were submerged in N-Methyl-2-Pyrrolidine (NMP) with stirring at room temperature for 24 hours. The samples were then rinsed in hot water at 70°C for 12 hours and baked in an oven at 120°C for 2 hours to remove residual solvent and moisture.

[0244] Figure 6A-Figure 6E are sample images with increasing PES content. From Figure 6A where the PES content is 30%, it can be observed that PES domains are isolated in the PEEK matrix; therefore, only surface regions of PES can be reached, and no interconnected porous structure was formed. For Figure 6B-Figure 6E, where PES contents are 40%, 50%, 60%, and 67%, respectively, a co-continuous structure is observed and a fully interconnected porous structure is obtained after leaching. The pore size increases from Figure 6A-Figure 6E. However, this could be due to the fact that PES content in the mixture is increased, and the effect of PES wt% on the annealing coarsening speed is not obvious. When PES phases are fully removed, it can be observed that the remaining PEEK phase is barely foamed, and almost all the foaming happens in the PES domain, which is consistent with the result in the previous section.

[0245] The initial sample weight and the final weight after leaching were recorded and the percent weight changes for different samples are shown in Figure 7. For the 30% PES sample, the PES phase is almost completely isolated and only the PES on the outer surface can be leached out. The 40% PES sample had a weight reduction of about 35% after leaching, suggesting that about 5% of the PES is in domains that are isolated in the PEEK matrix and cannot be reached by the solvent. For PEEK / PES blends that have a PES content of 50%, 60% and 67%, the weight reduction due to leaching is equal to the theoretical PES weight, with a difference within a 2% error. This shows that the PES content has been fully removed with the leaching process. For PES content higher than 70%, the PES phase will be dominant and PEEK phase will be dispersed within PES.

[0246] To demonstrate the need for solid-state foaming, un-foamed 50% PES samples were leached under the same conditions as foamed PEEK / PS samples. The result is also included in Figure 7. The sample weight before and after leaching is basically the same, showing that the solid-state foaming process can greatly improve the leaching speed of the PES phase.

[0247] Effect of Annealing conditions and PES wt% on Phase Morphology. The annealing conditions play the most important role to generate interconnected porous structures with controllable pore sizes. Heterogeneous polymer blends are non-equilibrium structures because of their large interfacial area. The interfacial tension can cause a reduction of interfacial area in the liquid blends causing the coarsening and retraction effects in immiscible polymer blends.

[0248] Figure 8A-Figure 8F are SEM images for 50 / 50 PEEK / PES mixtures with annealing times of 0, 15, 45, 90, 120, 180 minutes at an annealing temperature of 370°C, respectively. The scale bars for Figure 8 A and Figure 8B are 100 um, and the scale bars for Figure 8C-Figure 8F are 200 um for a better view of the microstructure.

[0249] From Figure 8A, it can be observed that the initial PEEK and PES phases are uniformly distributed across the cross-section with a small phase size of around 1 um. The initial morphology observed shows a co-continuous structure of PEEK and PES. As the annealing time increases, the pore size increases gradually, starting from an average of 20 um when annealed for 15 minutes, to about 100 um when annealed for 90-120 minutes and eventually goes up to more than 250 um when annealed for 180 minutes. The reason for the pore size increase is the coarsening effect during the quiescent annealing of immiscible blends. It can also be observed that the original co-continuous morphology is maintained and the two phases form an interconnected co-continuous morphology along with the pore growth. The interconnectivity can be observed from the inner structure in Figure 8A-Figure 8F after PES is leached and confirmed by the weight change shown in Figure 7.

[0250] In addition to the annealing time, the effect of annealing temperature on the phase morphology was studied. SEM images of annealing of the 50 / 50 PEEK / PES mixture at an annealing temperature of 350°C, 370°C, and 390°C for 90 minutes are shown in Figure 9A- Figure 9C, respectively.

[0251] The average pore sizes for different annealing times and different annealing temperatures were measured using Imaged, and the results are shown in Figure lOA-Figure 10B. From Figure 9A-Figure 9C and Figure 10B, it can be observed that even when the annealing time is the same, a higher annealing temperature tends to cause the pore sizes to grow larger. When the annealing temperature was 350°C, which is just above the melting point of PEEK, the pores generated after annealing 90 minutes were only about 20-30 um on average. When the annealing temperature was increased to 370°C and 390°C, the pore size increased significantly and reached 100-150 um. This is due to the fact that higher temperatures cause the coarsening effect of polymers to happen faster.

[0252] Based on the results from Figure 8A-Figure 8F, Figure 9A-Figure 9C, and Figure 10A- Figure 10B, it can be seen that although the pore growth rates are greatly different, the basic features of the coarsening phenomena are similar to previous reported immiscible blends [24, 29, 30, 32], It has been shown that the phase morphology change obeys Tomokita’s theory and the Cahn Hillard equation, which describe the phase size of immiscible blends grows with annealing time and annealing temperature. Based on these phenomena, pore size gradients are also achievable to produce functionally graded porous structure by applying temperature gradients during the annealing process.

[0253] Mechanical Properties of Leached and Non-Leached PEEK samples. Figure 11 shows the compressive test results of different fabricated porous PEEK samples. The compressive strength and modulus of these samples are summarized in Table 1. As a reference, fully dense PEEK samples made with as-received pellets were also tested. Since the PEEK phase is barely foamed, only about 10% total volume expansion was caused by the expansion of PES phase. The porosity of porous PEEK samples is close to the PES weight ratio after PES is fully leached. The porosity was measured by the leached PES weight ratio.

[0254] From Figure 11 and Table 1, it can be seen that the porous PEEK structure formed by the immiscible blend has a compressive strength of 8-26 MPa, a compressive modulus of 50-150 MPa, a porosity of 40%-67%, and a controllable pore size from 20-500 um or even higher.

[0255] Table 1. Mechanical properties of fabricated porous PEEK samples The porous structures made by the immiscible PEEK / PES blends with further compared with human trabecular bone and with porous PEEK made by existing methods [11, 12, 14, 18, 33-35]; the comparisons are shown in Table 2.

[0256] Table 2. Comparison of different porous PEEK structure

[0257] From the comparison in Table 2, it can be observed that the compressive strength of porous PEEK is similar to that of trabecular bone, which ranges from 1-12 MPa with an average of 3.9 MPa

[0036] , Comparing with other scaffolds and porous PEEK structures, the compressive strength of the porous PEEK structures made by immiscible blends described herein is higher than the strength of porous PEEK structured made by particle leaching. The compressive strength of the porous PEEK structures made by immiscible blends described herein is lower than that of 3D printed PEEK structures, which is 16-30 MPa; however, 3D printed PEEK scaffolds have much larger pore sizes that are not compatible with bone tissue engineering (Table 2).

[0258] The modulus of the porous PEEK prepared herein from immiscible blends is about 50- 150 MPa, which is similar to the value of 40-80 MPa for structures prepared using particle leaching and 70-110 MPa for structures prepared using just solid state foaming. However, the modulus is still lower than that of trabecular bone which ranges 80-800 MPa with average around 350 MPa. the as-received PEEK has a modulus of only 800 MPa, which is lower than standard PEEK modulus. One reason for the low compressive modulus can be due to the limit of PEEK material itself and the material grade used in the experiments herein. In addition, the low modulus can be due to the decrease of PEEK crystallinity after several treatments. Crystallinity plays an important role in the mechanical behavior of PEEK material, and the standard PEEK mechanical strength is referred to as highly crystallized PEEK with crystallinity of 35% or higher. During the experiments herein, the PEEK pellets were melt-extruded, annealed and foamed, which can change and decrease the crystallinity, resulting in lower mechanical strength compared to standard crystal PEEK. To increase the modulus and crystallinity of PEEK, some post treatments can be applied.

[0259] Natural trabecular bone has a pore size ranging from 50-850 um with most pore sizes lying in the range of 100-600 um, and the optimal pore size for tissue growth is around 100-400 um

[0037] , Particle leached PEEK structures can generate porous structure with a pore size from 300-600 um, which satisfies tissue growth requirements, but the strut size depends on the salt particle contact. The porosity for salt leaching samples cannot be lower than 70% due to the need of particle contact, which results in low mechanical strength. Solid-state foamed PEEK structures have pore sizes from 30-80 um, which are too small for tissue growth and the interconnectivity between pores are low. For 3D printed PEEK structures, with current printing machines, uniform pores can be produced, with the smallest pores about 300 um and precision extruded features of 500 um or higher. Using the immiscible blend method developed in this study, the pore size generated can be as small as 10 um and as large as 500 um by controlling the annealing conditions, which covers almost the whole range of trabecular bone pore sizes. In addition, random pores are generated from annealing and functionally graded pores can also be generated by applied gradient temperature during annealing, which can better mimic the natural bone structure and provide good potential for the need of custom designed implants.

[0260] Conclusion. A method of making interconnected porous PEEK is provided herein using an immiscible blend of PEEK and PES. The mixture of two incompatible molten polymers resulted in the interconnectivity of PEEK and PES phase when the weight ratio was 60% PEEK / 40% PES to 30% PEEK / 70% PES. N-Methyl-2-Pyrrolidine (NMP) was chosen to dissolve PES, since PES is soluble while PEEK is insoluble in NMP at room temperature. By controlling the annealing time and annealing temperature of the PEEK / PES mixture, the pore size can be controlled. By applying a temperature gradient, the annealing process can be used to generate a gradient porous structure, which further provides the possibility for custom implant designs. The study also revealed that when foaming the PEEK / PES mixture, only the PES phase would be foamed when the PES content is high. Solid-state foaming of the PEEK / PES mixture can greatly improve the leaching speed of PES phase while keeping the mechanical strength of the PEEK scaffold. The mechanical properties of the porous PEEK scaffold fabricated in this study were generally comparable to those of the trabecular bone. The fabrication method provides a large range of controllable pore sizes and has the ability to create functionally graded pores that mimic the natural bone structure. References

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[0297] Example 2 - 1 Method to Create Biomimetic Structure in High Strength Polymer for Bone Implants

[0298] Described herein is a fabrication method to create a biomimetic porous structure in a high strength polymer, Poly-ether-ether-ketone (PEEK). Recently PEEK became a popular candidate for medical implants due to its biocompatibility, mechanical strength, and X-ray transparency. However, there has not been an effective fabrication method to generate a biomimetic porous structure in PEEK to promote bone ingrowth. The lack of a biomimetic PEEK structure has resulted in poor bonding between natural bone and the implant, affecting the long-term effectiveness of bone repair. The method described here uses a specific sacrificial material and an appropriate solvent and can fabricate biomimetic PEEK implants with the help of solid-state foaming. The resulting porous implants retain a certain mechanical strength of PEEK and have interconnected porous structures resemble those found in natural bone.

[0299] Several methods have been used to generate porous PEEK structures. The most common method used currently is salt leaching, where a porous PEEK structure is created by using hot compression of cubic or spherical sodium chloride particles on a top and bottom layer of a solid PEEK block. The salt particles are then leached with water. A related method of generating a porous PEEK structure is solvent casting with particulate leaching, where PEEK is dissolved in organic solvent and cast on to water soluble particles such as salt. After drying and leaching, a highly porous PEEK structure can be obtained. Additive manufacturing is another method to fabricate porous PEEK structures. Among many additive manufacturing methods, fused deposition modeling (FDM) has been the most suitable method to print porous PEEK structures.

[0300] The hot compression and salt leaching methods only generate a thin layer (2 mm thick) of porous PEEK structure on the top and bottom surfaces of a PEEK block. The solvent casting and particulate leaching method can only generate porous PEEK structures of low strength due to the high porosity formed with the salt particle template. In addition, the morphology of the porous structure is determined by the shape and size of salt particles, which are often cubic. Three-dimensional printing methods, such as FDM, do not have sufficient resolution to fabricate biomimetic porous structure. The pore sizes generated with FDM are on the level of 400 um, which is much larger than those of natural bone.

[0301] Features of the methods described herein include generating a co-continuous polymer blend with PEEK and poly ether sulfone (PES), controlling the size of PES domain with thermal processing conditions, gas foaming of the polymer blend, and leach out the sacrificial PES phase with an appropriate solvent. The process is unique and solves the problems with the other methods described above.

[0302] The porous structure created with the methods described herein is fully interconnected with random pores, which mimics the structure of natural trabecular bone. The pore size can be controlled within a wide range of 20-500 um, which includes the 100-300 um range that is commonly believed for optimal tissue growth. The surface of the porous structure has a large concave curvature that benefits tissue growth. The porous structures have adjustable porosities ranging from 40-65% with different pore sizes, with good potential for customized implant designs. The sacrificial PES phase is fully amorphous, while the PEEK phase is semi-crystalline. The PES phase is easier to foam, which allows it to be rapidly removed in the leaching process.

[0303] The porous PEEK structure could be used for other applications such as filters and substrates for biochemical sensing.

[0304] Example 3 - High Strength Biomimetic Porous Polymer for Bone Tissue Engineering

[0305] Poly-ether-ether-ketone (PEEK) is a popular candidate for medical implants due to its biocompatibility, mechanical strength, and X-ray transparency. However, there has not been an effective fabrication method to create biomimetic porous structure in PEEK to promote bone ingrowth. The lack of biomimetic PEEK structure has resulted in poor bonding between natural bone and the implant, affecting the long-term effectiveness of bone repair.

[0306] The methods described herein combine polymer blending, solid-state foaming, and leaching to create porous PEEK implants with interconnected porous structures resembling those found in natural trabecular bone. It can be further combined with 3D printing to fabricate customized bone implant to promote interfacial bonding between the implant and natural bone.

[0307] The porous structure created with these methods is fully interconnected with random pores, which mimics the structure of natural trabecular bone. The adjustable pore size ranges from 20-500 um and the porosity from 40-65%. The surface of the porous structure has a large concave curvature that benefits tissue growth. The porous PEEK implant has high mechanical strength compared to other polymer implants and is X-ray transparent.

[0308] Benefits of the methods and devices described herein include, but are not limited to: Biomimetic random pores that mimic natural bone structure; Wide range of available pore sizes that cover the optimal range for tissue growth; Customizable implant design based on requirements; Mechanical strength similar to trabecular bone; and Cost efficient and eco- friendly. Markets include medical implant manufacture and PEEK spacers or cages.

[0309] Example 4 - A Method to Create Biomimetic Structure in High Strength Polymer for Bone Implants

[0310] Poly-ether-ether-ketone (PEEK) is a popular candidate for medical implants due to its biocompatibility, mechanical strength, and X-ray transparency. However, there is a lack of effective fabrication methods to create biomimetic porous structure in PEEK to promote bone ingrowth.

[0311] Described herein is a method that combines polymer blending, solid-state foaming, and leaching to create interconnected porous structures resembling those found in natural trabecular bone (vertebrae in the spinal column). The methods can be applicable to other bone types that are strong and porous.

[0312] All currently independent methods have their own drawbacks (e.g., thickness and strength).

[0313] This method can control pore size (20-500 um), creates adjustable porosities (40-65%) and a large concave curvature, and more thoroughly removes contaminants during the leaching process.

[0314] Example 5 - Biomimetic PEEK Implants Produced from Immiscible Blends

[0315] Biomimetic PEEK implants are fabricated through reducing PEEK / PES immiscible blends. This document compares this product and process against existing products and processes.

[0316] Product. Table 3 below shows a comparison of the PEEK scaffolds that are generated using the methods described herein and those generated with existing methods. Features that are important for bone implants and their desirable range are listed as criteria for comparison. While existing scaffolds satisfy certain criteria, none of them satisfies all the features falling within the desirable ranges. The method described herein is the only one that can produce scaffolds that satisfy all the criteria. Table 3: Comparison of scaffold generated by the methods described herein and generated by existing methods.

[0317] PEEK scaffolds generated by salt compression / salt porogen methods are the most common in the market. However, the minimum pore size these methods can achieve is 250 um. A pore size around 100 um is beneficial for the initial growth of bone tissue in the first 7 days. In addition, salt compress / salt porogen methods cannot generate gradient porous structures due to the challenge of manipulating salt particles of various sizes. A gradient porous structure is desirable for bone implants. Further, when salt particles are compressed through the whole scaffold and generate a fully interconnected structure, the porosity of the scaffold has to be at least 75%; otherwise, an interconnected structure cannot be achieved. Due to the high porosity, the compressive strength of the porous structure is only 2-5 MPa, much lower than the desired range.

[0318] Surface salt compression only generates a thin layer of 500-1000 um pores on the surface of the scaffold without a fully interconnected porous structure.

[0319] Current 3D printing techniques have a resolution around 400 um, and as a result can generate pores of 300 um or larger. Even though the pore size can be reduced by reducing the distance between filaments, the overall porosity will be greatly reduced to below 30% which is undesirable for bone implants. In addition, studies have shown that bone tissues tend to grow better on concave surfaces, instead of convex ones that are the characteristic of 3D printed PEEK scaffolds due to the shape of the filament.

[0320] Solid state foaming can generate porous structure for polymers; however, it mainly generates isolated pores with low interconnectivity. The surface roughness of the foamed product can be improved to improve cell attachment force. However, interconnected porous structure is required for tissue to grow into bone implants for better fixation.

[0321] Not included in Table 3, surface sulfonation is a surface treatment method that is used to improve surface roughness and help cell attachment. No interconnected structure for tissue ingrowth is generated with sulfonation.

[0322] Meanwhile, the methods described herein are able generate interconnected, gradient porous structure with a porosity of 50-70%. The pores have a concave surface, and the compressive strength of the scaffold is in the range of 7-26 MPa. These features are conducive to bone regeneration.

[0323] Process / Methods. The methods described herein combine the annealing of immiscible polymer blend with solid state foaming. Further, the process described herein involves materials and process parameters that are distinctive from published studies.

[0324] The methods described herein use a PEEK / PES, immiscible blending, annealing, optionally quenching, gas saturation, foaming, and leaching. This combination has not been described before.

[0325] First, the solid-state foaming behavior of PEEK / PES has never been revealed in literature before. Solid state foaming can improve the leaching speed of the sacrificed phase, in this case, PES, and further improve the porosity of the PEEK scaffold. Since PEEK is a semicrystalline polymer, its crystal regions make it hard to foam, while PES is fully amorphous and easy to foam. When foaming the PEEK / PES mixture, only the PES phase will foam, and PEEK is barely foamed. This effect can be beneficial to maintain mechanical strength for the scaffold which is important for bone implants. During preliminary tests, when instead a mixture of PEEK / PEI or PEEK / nylon was chosen, the foaming process foamed both phases and generated isolated pores in the PEEK phase as well. This greatly reduced the mechanical strength of the PEEK scaffold. This phenomenon also appears in foaming of polymers blends such as PLA / PVP and PLA / PS.

[0326] Second, an annealing and a quenching process are applied to the PEEK / PES mixture herein. Because PEEK is a semicrystalline polymer, the quenching process can help the polymer to maintain the phase morphology while controlling its crystallinity.

[0327] Example 6 - A 3D Printing-based Hybrid Manufacturing Method for High-strength Polymeric Medical Implant Fabrication

[0328] Abstract. This paper presents a 3D printing-based hybrid manufacturing method to fabricate high-strength polymeric medical implants. Poly-ether-ether-ketone (PEEK) and polyether sulfone (PES) are blended to make filament for use with the fused filament fabrication technique to print custom designed implants. After printing and annealing, PES is removed by leaching to create interconnected porous PEEK structure with suitable pore size and porosity for bone tissue ingrowth. The proposed method provides a versatile approach to fabricating medical implants that are both mechanically strong and microstructurally inducive to osseointegration. The polymeric implants are also X-ray transparent to allow post-surgery evaluations using an imaging method. An intervertebral spacer implant example is used to demonstrate the proposed fabrication method.

[0329] Introduction. High-strength medical implants, such as spinal implants, have been made of metals and solid polymers. Traditional metal implants, such as titanium orthopedic implants, provide excellent mechanical strength; however, their elastic modulus and hardness are too high compared with human bone. As a result, the metal implants may sink into the bone and cause irreversible damage [A1-A4], Metal implants are also less biocompatible and harder for osseointegration, i.e., the formation of direct structural and functional connection with the surrounding host bone [A4-A6], In addition, metal implants are opaque to X-ray, making it impossible to evaluate post-surgery recovery using an imaging method [A7, A8],

[0330] The most commonly used polymer for medical implants is polylactic acid (PLA), which is biocompatible, biodegradable, and suitable for resorbable implants in bone tissue engineering [A9, A10], However, PLA has a low mechanical strength and low corrosion resistance [Al l, A12], and thus not suitable for load bearing implant applications.

[0331] Poly-ether-ether-ketone (PEEK) is a biocompatible high-strength thermoplastic polymer that has been receiving growing attention recently for bone implants [A13-A15], Unlike metal implants, PEEK is X-ray transparent and does not cause artifacts in radiographic tests such as CT scans [Al 6], However, the chemical inertness of PEEK surface prevents osseointegration, resulting in poor cell attachment and greatly reduced bone bonding force [Al 7, Al 8],

[0332] To enhance the osseointegration of PEEK implants, a porous PEEK implant has to be proposed to facilitate cell ingrowth, nutrient diffusion, and waste exchange [Al 9, A20], Evans et al. [A21] applied hot compression to create a surface porous structure by compressing molten PEEK onto cubic or spherical sodium chloride particles and subsequently leaching the salt particles with water. Uddin et al. [A22] and Siddiq et al. [A23] dissolved PEEK in an organic solvent, mixed with salt particles, and cast the mixture into a mold. After the solvent was evaporated, the salt particles were removed with water. Both the hot-compaction and the solventcasting methods are limited to creating large pore sizes, exceeding 250 pm, and high porosity levels, ranging from 75% to 90%. Consequently, these scaffolds have a very low elastic modulus, making them less suitable for bone implant applications. 3D printing methods have been used to fabricate porous PEEK scaffolds for bone tissue engineering. Spece et al. [A24] and Zheng et al. [A25] used the fused filament fabrication (FFF) method to fabricate truss-lattice structures to allow bone ingrowth. However, the struts formed by FFF have a convex surface, which is not conducive to cell attachment. The resolution of the existing FFF method also makes it challenging to fabricate porous PEEK structures with balanced pore size and porosity that are suitable for bone tissue engineering [A26, A27], In this study, an implant fabrication method based on 3D printing and immiscible polymer blending is proposed. This hybrid manufacturing method provides a versatile approach to fabricating medical implants that are mechanically strong, highly inducive to osseointegration, and X-ray transparent. It also allows patient specific implants to be designed and fabricated using their own scanning data. The proposed fabrication process is demonstrated with an intervertebral spacer implant example as shown in Figure 12A-Figure 12B. Currently in transforaminal lumbar interbody fusion (TLIF) surgeries, a solid PEEK implant is inserted between two vertebrae (Figure 12A). To improve the osseointegration and bonding strength, a new implant is designed with both the solid and porous regions for load bearing and bone implant integration (Figure 12B). The geometry of the prototype is selected to mimic the shape of the lumber disc, as well as to demonstrate the capability of generating arbitrary geometry using the proposed method. The proposed fabrication process is studied, and the morphology and mechanical properties of the fabricated implant samples are characterized.

[0333] Experimental

[0334] The proposed fabrication process. Figure 13 shows the experimental setup of the proposed fabrication process for the new solid-porous PEEK implants. The FFF additive manufacturing method is used to print the implants with both neat PEEK filament and a custom- made filament from a mixture of PEEK and poly ether sulfone (PES). PEEK and PES form an immiscible polymer blend, and after printing PES can be removed by leaching to create an interconnected porous structure with suitable pore size and porosity for osseointegration. The neat PEEK filament forms a solid region of the implant for load bearing.

[0335] The PEEK / PES composite filament was made by blending PEEK and PES pellets in a twin-screw extruder (Thermal Science MiniLab II). The PEEK pellets were acquired from Victrex (Grade 450G) and PES pellets were Veradel A301NT. Before blending, both PEEK and PES pellets were dried at 150 °C for 24 hours. The blending temperature was set at 370 °C, the screw speed at 25 rpm, and blending time at 20 mins. After extrusion, the PEEK / PES filament was used to print the outer region of the designed intervertebral spacer implant using a CreatBot Fl 60 high temperature 3D printer. The resolution and printing speed limit of the 3D printer was 50 pm and 300 mm / s, respectively. The printing speed was chosen to be 15 mm / s to reduce vibration. A layer height of 200 pm and a 25% overlap was applied to ensure printing quality. The inner solid region was printed with neat PEEK filament (3DXTECH ThermaX). Due to equipment limitation, the two regions of the implant were printed separately and assembled after printing. With a multi-nozzle printer, the entire implant could be printed together.

[0336] After printing, the samples were annealed in a closed mold to achieve a bi-continuous phase structure in the PEEK / PES region. Annealed samples formed a solid skin that needed to be removed by machining. After removing the solid skin, the samples were leached with N-Methyl- 2 -Pyrrolidine (NMP) for 24 hours to remove the PES phase and obtain the porous PEEK structure. The samples were then rinsed with DI water and dried in an oven at 120 °C for 8 hours before characterization.

[0337] Sample characterization. The microstructures of fabricated samples were examined using a VEGA3 TESCAN scanning electron microscope (SEM). To prepare the sample crosssections, a freeze-fracturing procedure using liquid nitrogen was used, followed by sputtercoating of gold for SEM examination. The software ImageJ was used to measure the pore size of the porous PEEK structure. The weights of the sample before and after solvent leaching were measured and the difference was used to determine the porosity. Compression tests were performed on Instron 5980 to measure the elastic modulus and compressive strength. The samples were cut along the radial direction into approximately 4 mm x 4 mm x 4 mm blocks for compression tests. A preload of 10 N and a constant strain rate of 0.5 mm / min was applied in all the tests.

[0338] Results and Discussion

[0339] PEEK / PES filament. The PEEK / PES mixing condition included weight ratio, time, and extruder screw speed. Both PEEK and PES are high temperature thermoplastics, and they are immiscible under molten conditions. In this study, the mixing temperature was chosen to be 370 °C, and the screw speed and mixing time were fixed at 25 rpm and 20 mins, respectively. The weight ratio varied from 25 / 75 to 50 / 50 for PEEK / PES. Figure 14A-Figure 14B shows the results of filament making at different mixing weight ratios.

[0340] Effects of printing parameters. When using the 25 / 75 weight ratio, the extruded filament had inconsistent thicknesses and showed a pulsed wave shape as shown in Figure 14A. This was because PEEK and PES tended to expel each other during the mixing process. When mixing polymers using an extruder, a linear morphology will be achieved along the extrusion direction if the weight ratios of the two polymers are compatible and sufficient mixing time is applied.

[0341] When one polymer is significantly more than the other, the linear structure will break up to cause phase dispersion and the change of strength along the extrusion direction. Although a detailed study would be able to determine the optimal weight ratio for PEEK / PES filament making, a mixing ratio of 50 / 50 was used in this study to demonstrate the overall implant fabrication process. This 50 / 50 mixing ratio provided a consistent filament diameter at 1.75 mm, as shown in Figure 14B.

[0342] The printing parameters greatly affected the print quality. A high nozzle temperature and a proper path overlap were needed to achieve good print quality. In the study, a 20% path overlap was used to compensate for possible thickness variations of the filaments. Furthermore, although the melting temperature of PEEK is 340 °C and the glass transition temperature is 230 °C, a nozzle temperature of 430 °C was used to guarantee a consistent extrudate flow.

[0343] PEEK is a semi-crystal polymer, and the print quality is highly affected by its crystallinity. The higher the crystallinity, the higher the mechanical strength. Several studies have shown that to achieve high-crystallinity PEEK, the printer bed temperature needs to be at 130 °C or higher, and ideally the bed and chamber temperature both should be within 10 °C of the PEEK glass transition temperature. However, when printing PEEK / PES mixture in this study, it was noticed that if the bed and chamber temperatures were too high, the printed samples would have large distortions. This was because there existed large residual stress in the immiscible PEEK / PES blend, and as the temperature increased, the residual stress started to be released, causing large distortions for the printed samples.

[0344] As shown in Figure 15 A, when the bed temperature and chamber temperature were set at 130 °C, there was large distortions among the lower layers of the print. When the bed and chamber temperature were changed to 120 °C and 60 °C respectively, the distortion was greatly reduced, as can be seen in Figure 15B. Although a lower bed and chamber temperature can result in amorphous PEEK, which has a lower mechanical strength than crystalline PEEK, a post printing annealing step exists in the proposed fabrication process, which will compensate for the crystallinity loss. Thus, the lower chamber and bed temperatures were chosen to ensure geometrical accuracy.

[0345] In addition to temperatures, printing path also affected the print quality. Figure 16A shows that a zig-zag filling pattern resulted in rough surfaces and large gaps in the printed sample. This was due to the oscillation of the nozzle during printing. Figure 16B shows a circular printing path with several fillings at the comers. This path resulted in much better print quality.

[0346] Microstructure of fabricated samples. Figure 17A-Figure 17B shows a fabricated implant sample before and after the solid skin and the PES phase were removed. The fabricated sample was seen to have two distinct regions, a solid inner and a porous outer region. Machining of the solid skin did not cause smearing of the porous structure, due to the good machinability of PEEK. However, in addition to the desired smaller pores in the outer porous region, large bubbles were observed across the entire sample including the solid PEEK region. During the sample fabrication process, there were multiple steps that could introduce gas bubbles into the sample. First, there could be residual moisture in the filaments before the printing process. Second, there could be gaps in between partially fused filaments during the printing process. Third, air could be entrapped in the sample during the annealing process since a closed metal mold was used in the process to maintain sample geometry. The issue of large bubbles should be easily resolvable by further drying the material, using more appropriate chamber and bed temperatures, and providing an air vent during the annealing process. The darker area seen on the surface of the prototype in Figure 17B was due to contamination in the fabrication process. This can be resolved by using a stainless steel mold in the sample annealing process.

[0347] The cross-sectional view of the sample microstructure is shown in the SEM images in Figure 18. It can be seen that the solid and porous PEEK regions were completely fused together. After leaching of the PES phase, fully interconnected porous PEEK structure with a pore range of about 100-150 pm was achieved. This result demonstrated the feasibility of the hybrid manufacturing approach to fabricating customized bone implants.

[0348] Effects of annealing on pore size control. The optimal pore size range for bone tissue engineering is 100-300 pm [A26, A27], Therefore, it is important for an implant fabrication process to be able to control the pore size within this optimal pore size range for better cell attachment and growth. Since the PEEK / PES blends are non-equilibrium structures, an annealing process will reduce the interfacial tension, and thus the PEEK / PES interfacial area, leading to coarsening and retraction effects in the immiscible polymer blends.

[0349] Figure 19A-Figure 19C shows the SEM images of implant samples fabricated with a 50 / 50 PEEK / PES mixture under the same annealing temperature 370 °C, but different annealing times: 0, 45, 120 minutes. From Figure 19A, it can be seen that without annealing a very small pore size was obtained. As the annealing time increased, the pore size increased gradually, from a few micrometers with 0 min annealing to about 70 pm with 45 min annealing (Figure 19B) and above 100 pm with 120 min annealing (Figure 19C).

[0350] In addition to annealing time, the effect of annealing temperature was also studied, and the SEMs of the 50 / 50 PEEK / PES mixture annealed under 350 °C, 370 °C, and 390 °C for 90 minutes are shown in Figure 20A-Figure 20C. At 350 °C, the resulted pore size was approximately 20-30 pm. As the annealing temperature rose to 370 °C and 390 °C, the pore size increased to 75 pm and 125 pm, respectively.

[0351] The results for pore size control with annealing time and temperature are shown in Figure 21 A-Figure 21B. With annealing, a pore size as small as 10 pm and as large as 500 pm can be achieved by applying different annealing conditions, suggesting that the hybrid immiscible blend and 3D printing method is capable of fabricating patient specific bone implants with proper pore sizes for cell attachment and ingrowth. In addition, by applying a temperature gradient to the PEEK / PES mixture during the annealing process, a gradient porous structure can be generated. This will allow more flexibility for the proposed hybrid implant fabrication method.

[0352] Mechanical properties of fabricated PEEK implants. The mechanical test results of fabricated PEEK implant samples are shown in Figure 22 and Table 4. For comparison, the compressive strength and modulus of an entire porous PEEK sample without a solid region, as well as those of adult vertebral cancellous bone [A25], are also given in Table 4. The fabricated solid-porous implant samples had a 50% solid region and a 50% porous region, as has been shown in Figure 18. Both the porous PEEK sample and the porous region of the fabricated PEEK implant samples had a porosity of 50%.

[0353] Table 4. Compression test results

[0354] As shown in Table 4, the compressive strengths of the 3D printed implants are in the range of 32-40 MPa, about double that of porous PEEK of 50% porosity. The compressive modulus is about 620-700 MPa, which is close to seven times that of the porous PEEK sample. Both the porous PEEK sample and the 3D printed solid-porous PEEK implant have a much higher compressive strength than vertebral cancellous bone; however, the elastic modulus of the porous PEEK sample is much lower. The fabricated solid-porous PEEK implants, on the other hand, have a very similar elastic modulus as vertebral cancellous bone, suggesting that the fabricated PEEK implant in this study will be a much better candidate for spinal implants.

[0355] Conclusions. In this study, a manufacturing method of combining immiscible polymer blends with 3D printing is developed for medical implant fabrication. Experimental studies demonstrated that fully integrated high-strength polymeric bone implants comprising both a solid and porous region could be successfully fabricated, and the pore size could be controlled by annealing temperature and time. Mechanical test results suggested that the fabricated samples could be a much better candidate than solid PEEK or bulk porous PEEK samples for implants that require load bearing capabilities. The flexibility of the developed manufacturing method also allows for patient specific implants to be designed and fabricated with the patient’s own scanning data, enabling a much-needed technology for personalized medicine.

[0356] References

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[0382] EXEMPLARY ASPECTS

[0383] In view of the described porous polyether-ether-ketone (PEEK) scaffolds and methods of making and use thereof, herein below are described certain more particularly described aspects of the inventions. The particularly recited aspects should not, however, be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein or that the “particular” aspects are somehow limited in some way other than the inherent meanings of the language and formulas literally used therein.

[0384] Example 1 : A porous polyether-ether-ketone (PEEK) scaffold comprising: a continuous polyether-ether-ketone (PEEK) phase permeated by a continuous pore phase; wherein the continuous pore phase comprises a plurality of pores, the plurality of pores having an average pore size of from 20 to 600 micrometers (microns, pm); wherein the plurality of pores have a concave shape; wherein the porous PEEK scaffold has a porosity of from 40% to 90%; wherein the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa; and wherein the porous PEEK scaffold has a compressive modulus of from 50 to 150 MPa.

[0385] Example 2: The porous PEEK scaffold of any examples herein, particularly example 1, wherein the plurality of pores have an average pore size of from 10 to 600 micrometers.

[0386] Example 3 : The porous PEEK scaffold of any examples herein, particularly example 1 or example 2, wherein the plurality of pores have an average pore size of from 20 to 500 micrometers.

[0387] Example 4: The porous PEEK scaffold of any examples herein, particularly examples 1-3, wherein the plurality of pores have an average pore size of from 100 to 400 micrometers.

[0388] Example 5: The porous PEEK scaffold of any examples herein, particularly examples 1-4, wherein the plurality of pores have an average pore size of from 100 to 300 micrometers. Example 6: The porous PEEK scaffold of any examples herein, particularly examples 1-5, wherein the plurality of pores have an average pore size that varies across a dimension of the porous PEEK scaffold, such that the plurality of pores has an average pore size gradient from an initial average pore size to a final average pore size.

[0389] Example 7: The porous PEEK scaffold of any examples herein, particularly example 6, wherein the average pore size gradient comprises a radial gradient, a linear gradient, a stepped gradient, an exponential gradient, a logarithmic gradient, or a combination thereof.

[0390] Example 8: The porous PEEK scaffold of any examples herein, particularly examples 1-7, wherein the porous PEEK scaffold has a porosity of from 40% to 70%.

[0391] Example 9: The porous PEEK scaffold of any examples herein, particularly examples 1-8, wherein the porous PEEK scaffold has a porosity of from 40% to 65%.

[0392] Example 10: The porous PEEK scaffold of any examples herein, particularly examples 1-9, wherein the porous PEEK scaffold has a porosity of from 50% to 70%.

[0393] Example 11 : The porous PEEK scaffold or any examples herein, particularly examples 1-10, wherein the porous PEEK scaffold has a compressive strength of from 8 to 26 MPa.

[0394] Example 12: The porous PEEK scaffold of any examples herein, particularly examples 1-11, wherein the porous PEEK scaffold is biocompatible, biomimetic, or a combination thereof.

[0395] Example 13: The porous PEEK scaffold of any examples herein, particularly examples 1-12, wherein the porous PEEK scaffold further comprises a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof.

[0396] Example 14: The porous PEEK scaffold of any examples herein, particularly examples 1-13, wherein the porous PEEK scaffold further comprises a mineral, such as hydroxyapatite (HA), mixed in the matrix or coated on the inner surface of the pores, for example to improve biocompatibility and / or cell attachment.

[0397] Example 15: A method of use of the porous PEEK scaffold of any examples herein, particularly examples 1-14.

[0398] Example 16: The method of any examples herein, particularly example 15, wherein the method comprises using the porous PEEK scaffold as a tissue engineering scaffold.

[0399] Example 17: The method of any examples herein, particularly example 15 or example 16, wherein the method comprises using the porous PEEK scaffold as a bone implant, such as a trabecular bone implant.

[0400] Example 18: The method of any examples herein, particularly examples 15-17, wherein the method comprises using the porous PEEK scaffold as a cervical disc spacer or cage. Example 19: The method of any examples herein, particularly examples 15-18, wherein the method comprises assembling the porous PEEK scaffold together with a solid PEEK structure to fabricate an implant, such as a bone implant, for example a cervical disc spacer.

[0401] Example 20: The method of any examples herein, particularly examples 15-19, wherein the method comprises assembling the porous PEEK scaffold together with a 3D printed structure, which can be dense or porous, to fabricate a customized implant, such as a bone implant, for example a cervical disc spacer.

[0402] Example 21 : The method of any examples herein, particularly example 15, wherein the method comprises using the porous PEEK scaffold as a filter, as a substrate for biochemical sensing, or a combination thereof.

[0403] Example 22: An article of manufacture or a device comprising the porous PEEK scaffold of any examples herein, particularly examples 1-14.

[0404] Example 23 : The article or device of any examples herein, particularly example 22, wherein the article or device comprises a tissue engineering scaffold.

[0405] Example 24: The article or device of any examples herein, particularly example 22 or example 23, wherein the article or device comprises a bone implant, such as a trabecular bone implant.

[0406] Example 25: The article or device of any examples herein, particularly examples 22-24, wherein the article or device comprises a cervical disc spacer or cage.

[0407] Example 26: The article or device of any examples herein, particularly examples 22-25, wherein the article or device comprises the porous PEEK scaffold assembled together with a solid PEEK structure, the assembly being an implant, such as a bone implant, for example a cervical disc spacer.

[0408] Example 27: The article or device of any examples herein, particularly examples 22-26, wherein the article or device comprises the porous PEEK scaffold assembled together with a 3D printed structure, which can be dense or porous, the assembly being a customized implant, such as a bone implant, for example a cervical disc spacer.

[0409] Example 28: The article or device of any examples herein, particularly example 22, wherein the article or device comprises a filter, a substrate for biochemical sensing, or a combination thereof.

[0410] Example 29: A method of making the porous polyether-ether-ketone (PEEK) scaffold of any examples herein, particularly examples 1-14, the method comprising: blending polyether- ether-ketone (PEEK) and polyether sulfone (PES) together at a blending temperature to form an immiscible co-continuous blend comprising PEEK and PES, wherein the immiscible co- continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 30:70 to 70:30; annealing the immiscible blend at an annealing temperature, thereby forming an annealed composition; saturating the annealed composition with a gas, thereby forming a gas saturated composition; solid state foaming the gas saturated composition, thereby forming a foamed composition, wherein the foamed composition comprises a foamed PES phase and a substantially unfoamed PEEK phase; and exposing the foamed composition to a solvent thereby leaching the foamed PES phase to form the porous PEEK scaffold.

[0411] Example 30: The method of any examples herein, particularly example 29, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 40:60 to 70:30.

[0412] Example 31 : The method of any examples herein, particularly example 29 or example 30, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 40:60 to 67:33.

[0413] Example 32: The method of any examples herein, particularly examples 29-31, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 50:50 to 70:30.

[0414] Example 33: The method of any examples herein, particularly examples 29-32, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 50:50 to 67:33.

[0415] Example 34: The method of any examples herein, particularly examples 29-33, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of 40:60, 50:50, 60:40, or 67:33.

[0416] Example 35: The method of any examples herein, particularly examples 29-34, wherein the blending is accomplished using an extruder, such as a twin-screw extruder.

[0417] Example 36: The method of any examples herein, particularly examples 29-35, wherein the blending temperature is from 350°C to 400°C, or from 350°C to 390°C, such as 370°C.

[0418] Example 37: The method of any examples herein, particularly examples 29-36, wherein the PEEK and PES are blended for an amount of time of from 1 minute to 1 hour, or from 1 minute to 30 minutes, such as 20 minutes.

[0419] Example 38: The method of any examples herein, particularly examples 29-37, wherein the PEEK is premixed (e.g., before blending with PES) with a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof. Example 39: The method of any examples herein, particularly examples 29-38, wherein the method further comprises blending PEEK and PES together with a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof.

[0420] Example 40: The method of any examples herein, particularly example 38 or example 39, wherein the method further comprises selecting to include the strengthening additive, the identity of the strengthening additive, the amount of the strengthening additive, or a combination thereof, for example in order to improve the mechanical strength of the porous PEEK scaffold, e.g. to a predetermined value.

[0421] Example 41 : The method of any examples herein, particularly examples 29-40, wherein the PEEK is premixed (e.g., before blending with PES) with a mineral, such as hydroxyapatite (HA), for example to improve the biocompatibility and / or cell attachment to the porous PEEK scaffold.

[0422] Example 42: The method of any examples herein, particularly examples 29-41, wherein the method further comprises blending PEEK and PES together with a mineral, such as hydroxyapatite (HA), for example to improve the biocompatibility and / or cell attachment to the porous PEEK scaffold.

[0423] Example 43 : The method of any examples herein, particularly examples 29-42, wherein the annealing comprises quiescent annealing.

[0424] Example 44: The method of any examples herein, particularly examples 29-43, wherein the annealing temperature is from 340°C to 400°C, or from 350°C to 390°C, such as from 360°C to 370°C.

[0425] Example 45: The method of any examples herein, particularly examples 29-44, wherein the annealing temperature varies across a dimension, such that the immiscible blend is annealed using an annealing temperature gradient.

[0426] Example 46: The method of any examples herein, particularly example 45, wherein the annealing temperature gradient comprises a radial gradient, a linear gradient, a stepped gradient, an exponential gradient, a logarithmic gradient, or a combination thereof.

[0427] Example 47: The method of any examples herein, particularly examples 29-46, wherein the immiscible blend is annealed for an amount of time of 1 minute to 12 hours, such as from 1 minute to 6 hours.

[0428] Example 48: The method of any examples herein, particularly examples 29-47, wherein the immiscible blend is annealed for an amount of time of from 15 minutes to 180 minutes, such as from 90 minutes to 180 minutes. Example 49: The method of any examples herein, particularly examples 29-48, wherein the immiscible blend is annealed for an amount of time of from 90 minutes to 180 minutes and the annealing temperature is from 360°C to 370°C.

[0429] Example 50: The method of any examples herein, particularly examples 29-49, wherein the annealing conditions (e.g., time and / or temperature) are selected to control the porosity, the average pore size, or a combination thereof.

[0430] Example 51 : The method of any examples herein, particularly examples 29-50, wherein the method further comprises, before saturating with a gas, quenching the annealed composition, thereby forming a quenched composition, and then saturating the quenched composition with a gas to form the gas saturated composition.

[0431] Example 52: The method of any examples herein, particularly example 51, wherein quenching the annealed composition comprises submersing the annealed composition in a bath having a temperature of from 0°C to 30°C (e.g., from 0°C to 15°C) for an amount of time of from 1 second to 30 seconds.

[0432] Example 53: The method of any examples herein, particularly examples 29-52, wherein saturating the quenched composition or the annealed composition with a gas comprises placing the quenched composition or the annealed composition in a high pressure vessel and exposing the quenched composition or the annealed composition to CO2 (such as supercritical CO2) at a pressure of from 5 to 20 MPa for an amount of time of from 24 hours to 120 hours.

[0433] Example 54: The method of any examples herein, particularly example 53, wherein the amount of time is from 60 hours to 84 hours, such as 72 hours.

[0434] Example 55: The method of any examples herein, particularly examples 29-54, wherein saturating the quenched composition or the annealed composition with a gas comprises placing the quenched composition or the annealed composition in a high pressure vessel and exposing the quenched composition or the annealed composition to CO2 (such as supercritical CO2) at a pressure of from 5 to 20 MPa for an amount of time such that the composition has an equilibrium gas concentration for 24 hours.

[0435] Example 56: The method of any examples herein, particularly examples 29-55, wherein the gas saturation is performed at a temperature of 35°C.

[0436] Example 57: The method of any examples herein, particularly examples 29-56, wherein solid state foaming comprises placing the gas saturated composition in a bath having a temperature of from 200°C to 350°C, from 300°C to 350°C, or from 330°C to 340°C.

[0437] Example 58: The method of any examples herein, particularly example 57, wherein the bath comprises a molten salt mixture. Example 59: The method of any examples herein, particularly example 57 or example 58, wherein the gas saturated composition is placed in the bath for an amount of time of from 1 second to 30 seconds.

[0438] Example 60: The method of any examples herein, particularly example 59, wherein the gas saturated composition is placed in the bath for an amount of time of from 1 second to 15 seconds, such as 7 seconds.

[0439] Example 61 : The method of any examples herein, particularly examples 29-60, wherein the foamed PES phase comprises from 90-100% of the PES (e.g., from 90-100% of the PES is foamed).

[0440] Example 62: The method of any examples herein, particularly examples 29-61, wherein exposing the foamed composition to the solvent comprises submersing the foamed composition in the solvent.

[0441] Example 63 : The method of any examples herein, particularly examples 29-62, wherein the solvent comprises N-Methyl-2-Pyrrolidine (NMP).

[0442] Example 64: The method of any examples herein, particularly examples 29-63, wherein the foamed composition is exposed to the solvent for an amount of time of from 4 to 26 hours, or from 12 hours to 36 hours, such as 24 hours.

[0443] Example 65: The method of any examples herein, particularly examples 29-64, wherein leaching removes 90-100% of the foamed PES.

[0444] Example 66: The method of any examples herein, particularly examples 29-65, wherein the porous PEEK scaffold is substantially free of PES.

[0445] Example 67: The method of any examples herein, particularly examples 29-66, wherein, after leaching, the porous PEEK scaffold is rinsed and dried.

[0446] Example 68: The method of any examples herein, particularly example 67, wherein the porous PEEK scaffold is rinsed by submersing the porous PEEK scaffold in water (e.g., at 75°C) for an amount of time (e.g., 24 hours) to fully remove the solvent.

[0447] Example 69: The method of any examples herein, particularly example 67 or example 68, wherein drying comprises baking in an oven (e.g., at 120°C for 8 hours) to remove moisture.

[0448] Example 70: The method of any examples herein, particularly examples 29-69, wherein, after leaching and / or drying, the method further comprises post-treating the porous PEEK scaffold, for example to improve a property of the porous PEEK scaffold.

[0449] Example 71 : The method of any examples herein, particularly examples claims 29-70, wherein, after blending and before annealing, the method further comprises extruding the immiscible blend into a filament (e.g., a filament comprising the immiscible blend). Example 72: The method of any examples herein, particularly example 71, wherein, after forming the filament and before annealing, the method further comprises using the filament for 3D printing, for example for form a 3D printed implant comprising the immiscible blend.

[0450] Other advantages which are obvious and which are inherent to the invention will be evident to one skilled in the art. It will be understood that certain features and sub-combinations are of utility and may be employed without reference to other features and sub-combinations. This is contemplated by and is within the scope of the claims. Since many possible embodiments may be made of the invention without departing from the scope thereof, it is to be understood that all matter herein set forth or shown in the accompanying drawings is to be interpreted as illustrative and not in a limiting sense.

[0451] The methods of the appended claims are not limited in scope by the specific methods described herein, which are intended as illustrations of a few aspects of the claims and any methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative method steps disclosed herein are specifically described, other combinations of the method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

Claims

CLAIMSWhat is claimed is:

1. A porous polyether-ether-ketone (PEEK) scaffold comprising: a continuous polyether-ether-ketone (PEEK) phase permeated by a continuous pore phase; wherein the continuous pore phase comprises a plurality of pores, the plurality of pores having an average pore size of from 20 to 600 micrometers (microns, pm); wherein the plurality of pores have a concave shape; wherein the porous PEEK scaffold has a porosity of from 40% to 90%; wherein the porous PEEK scaffold has a compressive strength of from 1 to 30 MPa; and wherein the porous PEEK scaffold has a compressive modulus of from 50 to 150 MPa.

2. The porous PEEK scaffold of claim 1, wherein the plurality of pores have an average pore size of from 10 to 600 micrometers.

3. The porous PEEK scaffold of claim 1 or claim 2, wherein the plurality of pores have an average pore size of from 20 to 500 micrometers.

4. The porous PEEK scaffold of any one of claims 1-3, wherein the plurality of pores have an average pore size of from 100 to 400 micrometers.

5. The porous PEEK scaffold of any one of claims 1-4, wherein the plurality of pores have an average pore size of from 100 to 300 micrometers.

6. The porous PEEK scaffold of any one of claims 1-5, wherein the plurality of pores have an average pore size that varies across a dimension of the porous PEEK scaffold, such that the plurality of pores has an average pore size gradient from an initial average pore size to a final average pore size.

7. The porous PEEK scaffold of claim 6, wherein the average pore size gradient comprises a radial gradient, a linear gradient, a stepped gradient, an exponential gradient, a logarithmic gradient, or a combination thereof.

8. The porous PEEK scaffold of any one of claims 1-7, wherein the porous PEEK scaffold has a porosity of from 40% to 70%.

9. The porous PEEK scaffold of any one of claims 1-8, wherein the porous PEEK scaffold has a porosity of from 40% to 65%.

10. The porous PEEK scaffold of any one of claims 1-9, wherein the porous PEEK scaffold has a porosity of from 50% to 70%.

11. The porous PEEK scaffold of any one of claims 1-10, wherein the porous PEEK scaffold has a compressive strength of from 8 to 26 MPa.

12. The porous PEEK scaffold of any one of claims 1-11, wherein the porous PEEK scaffold is biocompatible, biomimetic, or a combination thereof.

13. The porous PEEK scaffold of any one of claims 1-12, wherein the porous PEEK scaffold further comprises a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof.

14. The porous PEEK scaffold of any one of claims 1-13, wherein the porous PEEK scaffold further comprises a mineral, such as hydroxyapatite (HA), mixed in the matrix or coated on the inner surface of the pores, for example to improve biocompatibility and / or cell attachment.

15. A method of use of the porous PEEK scaffold of any one of claims 1-14.

16. The method of claim 15, wherein the method comprises using the porous PEEK scaffold as a tissue engineering scaffold.

17. The method of claim 15 or claim 16, wherein the method comprises using the porous PEEK scaffold as a bone implant, such as a trabecular bone implant.

18. The method of any one of claims 15-17, wherein the method comprises using the porous PEEK scaffold as a cervical disc spacer or cage.

19. The method of any one of claims 15-18, wherein the method comprises assembling the porous PEEK scaffold together with a solid PEEK structure to fabricate an implant, such as a bone implant, for example a cervical disc spacer.

20. The method of any one of claims 15-19, wherein the method comprises assembling the porous PEEK scaffold together with a 3D printed structure, which can be dense or porous, to fabricate a customized implant, such as a bone implant, for example a cervical disc spacer.

21. The method of claim 15, wherein the method comprises using the porous PEEK scaffold as a filter, as a substrate for biochemical sensing, or a combination thereof.

22. An article of manufacture or a device comprising the porous PEEK scaffold of any one of claims 1-14.

23. The article or device of claim 22, wherein the article or device comprises a tissue engineering scaffold.

24. The article or device of claim 22 or claim 23, wherein the article or device comprises a bone implant, such as a trabecular bone implant.

25. The article or device of any one of claims 22-24, wherein the article or device comprises a cervical disc spacer or cage.

26. The article or device of any one of claims 22-25, wherein the article or device comprises the porous PEEK scaffold assembled together with a solid PEEK structure, the assembly being an implant, such as a bone implant, for example a cervical disc spacer.

27. The article or device of any one of claims 22-26, wherein the article or device comprises the porous PEEK scaffold assembled together with a 3D printed structure, which can be dense or porous, the assembly being a customized implant, such as a bone implant, for example a cervical disc spacer.

28. The article or device of claim 22, wherein the article or device comprises a filter, a substrate for biochemical sensing, or a combination thereof.

29. A method of making the porous polyether-ether-ketone (PEEK) scaffold of any one of claims 1-14, the method comprising: blending polyether-ether-ketone (PEEK) and polyether sulfone (PES) together at a blending temperature to form an immiscible co-continuous blend comprising PEEK and PES, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 30:70 to 70:30; annealing the immiscible blend at an annealing temperature, thereby forming an annealed composition; saturating the annealed composition with a gas, thereby forming a gas saturated composition;solid state foaming the gas saturated composition, thereby forming a foamed composition, wherein the foamed composition comprises a foamed PES phase and a substantially unfoamed PEEK phase; and exposing the foamed composition to a solvent thereby leaching the foamed PES phase to form the porous PEEK scaffold.

30. The method of claim 29, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 40:60 to 70:30.

31. The method of claim 29 or claim 30, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 40:60 to 67:33.

32. The method of any one of claims 29-31, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 50:50 to 70:30.

33. The method of any one of claims 29-32, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of from 50:50 to 67:33.

34. The method of any one of claims 29-33, wherein the immiscible co-continuous blend comprises PES and PEEK in a weight ratio (PES:PEEK) of 40:60, 50:50, 60:40, or 67:33.

35. The method of any one of claims 29-34, wherein the blending is accomplished using an extruder, such as a twin-screw extruder.

36. The method of any one of claims 29-35, wherein the blending temperature is from 350°C to 400°C, or from 350°C to 390°C, such as 370°C.

37. The method of any one of claims 29-36, wherein the PEEK and PES are blended for an amount of time of from 1 minute to 1 hour, or from 1 minute to 30 minutes, such as 20 minutes.

38. The method of any one of claims 29-37, wherein the PEEK is premixed (e.g., before blending with PES) with a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof.

39. The method of any one of claims 29-38, wherein the method further comprises blending PEEK and PES together with a strengthening additive, such as a mineral (e.g., hydroxyapatite (HA)), glass fibers, or a combination thereof.

40. The method of claim 38 or claim 39, wherein the method further comprises selecting to include the strengthening additive, the identity of the strengthening additive, the amount of the strengthening additive, or a combination thereof, for example in order to improve the mechanical strength of the porous PEEK scaffold, e.g. to a predetermined value.

41. The method of any one of claims 29-40, wherein the PEEK is premixed (e.g., before blending with PES) with a mineral, such as hydroxyapatite (HA), for example to improve the biocompatibility and / or cell attachment to the porous PEEK scaffold.

42. The method of any one of claims 29-41, wherein the method further comprises blending PEEK and PES together with a mineral, such as hydroxyapatite (HA), for example to improve the biocompatibility and / or cell attachment to the porous PEEK scaffold.

43. The method of any one of claims 29-42, wherein the annealing comprises quiescent annealing.

44. The method of any one of claims 29-43, wherein the annealing temperature is from 340°C to 400°C, or from 350°C to 390°C, such as from 360°C to 370°C.

45. The method of any one of claims 29-44, wherein the annealing temperature varies across a dimension, such that the immiscible blend is annealed using an annealing temperature gradient.

46. The method of claim 45, wherein the annealing temperature gradient comprises a radial gradient, a linear gradient, a stepped gradient, an exponential gradient, a logarithmic gradient, or a combination thereof.

47. The method of any one of claims 29-46, wherein the immiscible blend is annealed for an amount of time of 1 minute to 12 hours, such as from 1 minute to 6 hours.

48. The method of any one of claims 29-47, wherein the immiscible blend is annealed for an amount of time of from 15 minutes to 180 minutes, such as from 90 minutes to 180 minutes.

49. The method of any one of claims 29-48, wherein the immiscible blend is annealed for an amount of time of from 90 minutes to 180 minutes and the annealing temperature is from 360°C to 370°C.

50. The method of any one of claims 29-49, wherein the annealing conditions (e.g., time and / or temperature) are selected to control the porosity, the average pore size, or a combination thereof.

51. The method of any one of claims 29-50, wherein the method further comprises, before saturating with a gas, quenching the annealed composition, thereby forming a quenched composition, and then saturating the quenched composition with a gas to form the gas saturated composition.

52. The method of claim 51, wherein quenching the annealed composition comprises submersing the annealed composition in a bath having a temperature of from 0°C to 30°C (e.g., from 0°C to 15°C) for an amount of time of from 1 second to 30 seconds.

53. The method of any one of claims 29-52, wherein saturating the quenched composition or the annealed composition with a gas comprises placing the quenched composition or the annealed composition in a high pressure vessel and exposing the quenched composition or the annealed composition to CO2 (such as supercritical CO2) at a pressure of from 5 to 20 MPa for an amount of time of from 24 hours to 120 hours.

54. The method of claim 53, wherein the amount of time is from 60 hours to 84 hours, such as 72 hours.

55. The method of any one of claims 29-54, wherein saturating the quenched composition or the annealed composition with a gas comprises placing the quenched composition or the annealed composition in a high pressure vessel and exposing the quenched composition or the annealed composition to CO2 (such as supercritical CO2) at a pressure of from 5 to 20 MPa for an amount of time such that the composition has an equilibrium gas concentration for 24 hours.

56. The method of any one of claims 29-55, wherein the gas saturation is performed at a temperature of 35°C.

57. The method of any one of claims 29-56, wherein solid state foaming comprises placing the gas saturated composition in a bath having a temperature of from 200°C to 350°C, from 300°C to 350°C, or from 330°C to 340°C.

58. The method of claim 57, wherein the bath comprises a molten salt mixture.

59. The method of claim 57 or claim 58, wherein the gas saturated composition is placed in the bath for an amount of time of from 1 second to 30 seconds.

60. The method of claim 59, wherein the gas saturated composition is placed in the bath for an amount of time of from 1 second to 15 seconds, such as 7 seconds.

61. The method of any one of claims 29-60, wherein the foamed PES phase comprises from 90-100% of the PES (e.g., from 90-100% of the PES is foamed).

62. The method of any one of claims 29-61, wherein exposing the foamed composition to the solvent comprises submersing the foamed composition in the solvent.

63. The method of any one of claims 29-62, wherein the solvent comprises N-Methyl-2- Pyrrolidine (NMP).

64. The method of any one of claims 29-63, wherein the foamed composition is exposed to the solvent for an amount of time of from 4 to 26 hours, or from 12 hours to 36 hours, such as 24 hours.

65. The method of any one of claims 29-64, wherein leaching removes 90-100% of the foamed PES.

66. The method of any one of claims 29-65, wherein the porous PEEK scaffold is substantially free of PES.

67. The method of any one of claims 29-66, wherein, after leaching, the porous PEEK scaffold is rinsed and dried.

68. The method of claim 67, wherein the porous PEEK scaffold is rinsed by submersing the porous PEEK scaffold in water (e.g., at 75°C) for an amount of time (e.g., 24 hours) to fully remove the solvent.

69. The method of claim 67 or claim 68, wherein drying comprises baking in an oven (e.g., at 120°C for 8 hours) to remove moisture.

70. The method of any one of claims 29-69, wherein, after leaching and / or drying, the method further comprises post-treating the porous PEEK scaffold, for example to improve a property of the porous PEEK scaffold.

71. The method of any one of claims 29-70, wherein, after blending and before annealing, the method further comprises extruding the immiscible blend into a filament (e.g., a filament comprising the immiscible blend).

72. The method of claim 71, wherein, after forming the filament and before annealing, the method further comprises using the filament for 3D printing, for example for form a 3D printed implant comprising the immiscible blend.

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