Patent Application
20220125990
The present disclosure relates to systems and methods for hot-isostatic pressing to increase the nitrogen content in ceramics and glasses. Aspects of the disclosure relate to components or implants produced by the systems and methods disclosed herein.
The need for safe and reliable inactivation of viruses and lysis, of bacteria, and fungi is universal. There is a broad need to control the pathogens that affect human health and agricultural products. There is a need for improved and varied methods for manufacturing compounds, materials, or components that possess antipathogenic properties for biomedical implants, devices, and fomites.
The present disclosure relates to methods and systems for manufacturing a compound, material, or component, and particularly to manufacturing a compound, material, or component using hot-isostatic pressing with non-adiabatic cooling. Aspects of the disclosure also relate to compounds, materials, components or implants produced by the methods disclosed herein.
The methods for manufacturing a compound, material, component, or implant disclosed herein advantageously enable their saturation with nitrogen. In addition, the methods disclosed herein enable the production of compounds, materials, components or implants with increased antipathogenic properties due to the increased nitrogen content. The methods of manufacture utilize a unique process to produce compounds, materials, components or implants that simultaneously have increased density, supersaturation of nitrogen, and improved anti-pathogenicity, which is highly desirable. In some instances, the components may be configured to be implants supersaturated with nitrogen, which is desirable for prosthetic dental implants, spinal implants, total joint implants, and the like.
In accordance with a first aspect, a method for manufacturing a component comprising a ceramic or glass material typically includes placing the ceramic or glass compound, material, or component made from the ceramic or glass compound or material, within a containment vessel; simultaneously heating and applying isostatic pressure to the ceramic or glass compound, material, or component within the containment vessel to a first temperature and a first pressure using pressurizing nitrogen gas; holding the first temperature and the first pressure for a period of time; cooling the ceramic or glass material within the containment vessel to a second temperature while maintaining the first pressure; and depressurizing the containment vessel to a second pressure. The finished component comprises the ceramic or glass compound, material, or component supersaturated with nitrogen.
The method may further include removing the compound, material, or component from the containment vessel. The ceramic or glass material may be a powder and may include silicon nitride. In some aspects, the ceramic or glass material may be sintered prior to being received within the containment vessel and/or the component may be pre-formed into a useful shape prior to being received within the containment vessel.
In various embodiments, the first temperature may be about 1800° C., the second temperature may be less than 100° C., the first pressure may be about 200 MPa, the second pressure may be about atmospheric pressure, and the period of time may be about 2 hours.
In some aspects, the cooling step increases an average flexural strength of the component by 200-300 MPa as compared to a component produced using adiabatic cooling.
According to a second aspect, provided is an implant that is produced by a method, which includes preforming a ceramic or glass material into a useful shape, placing the preformed ceramic or glass material within a containment vessel; simultaneously heating and applying isostatic pressure to the preformed ceramic or glass material within the containment vessel to a first temperature and a first pressure using pressurizing nitrogen gas; holding the first temperature and the first pressure for a period of time; cooling the ceramic or glass material within the containment vessel to a second temperature while maintaining the first pressure; and depressurizing the containment vessel to a second pressure. In some aspects, the compound, material, component, or implant may be silicon nitride (Si3N4) with further additions of about 0.1 wt. % or more of sodium oxide (Na2O), lithium oxide (Li2O), potassium oxide (K2O) magnesium oxide (MgO), aluminum oxide (Al2O3), yttrium oxide (Y2O3), ytterbium oxide (Yb2O3), lanthanum oxide (La2O3), strontium oxide (SrO), calcium oxide (CaO), silicon dioxide (SiO2), zirconium oxide (ZrO2), boron trioxide (B2O3), phosphorus pentoxide (P2O5) or combinations thereof.
Preferably, the compound, material, component or implant may be antipathogenic. For instance, the compound, material, component or implant may inhibit the proliferation of at least one of bacteria, fungi, and viruses.
In some aspects, the implant has an average flexural strength that is 200-300 MPa higher than an implant produced using adiabatic cooling.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description serve to explain the principles of the invention.
It should be understood that the various aspects are not limited to the arrangements shown in the drawings.
Various embodiments of the disclosure are discussed in detail below. While specific implementations are discussed, it should be understood that this is done for illustration purposes only. A person skilled in the relevant art will recognize that other components and configurations may be used without parting from the spirit and scope of the disclosure. Thus, the following description and drawings are illustrative and are not to be construed as limiting. Numerous specific details are described to provide a thorough understanding of the disclosure. However, in certain instances, well-known or conventional details are not described in order to avoid obscuring the description.
Reference to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments. Moreover, various features are described which may be exhibited by some embodiments and not by others. Thus, references to one or an embodiment in the present disclosure can be references to the same embodiment or any embodiment; and, such references mean at least one of the embodiments.
The terms used in this specification generally have their ordinary meanings in the art, within the context of the disclosure, and in the specific context where each term is used. Alternative language and synonyms may be used for any one or more of the terms discussed herein, and no special significance should be placed upon whether or not a term is elaborated or discussed herein. In some cases, synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and is not intended to further limit the scope and meaning of the disclosure or of any example term. Likewise, the disclosure is not limited to various embodiments given in this specification.
As used herein, “about” refers to numeric values, including whole numbers, fractions, percentages, etc., whether or not explicitly indicated. The term “about” generally refers to a range of numerical values, for instance, ±0.5-1%, ±1-5% or ±5-10% of the recited value, that one would consider equivalent to the recited value, for example, having the same function or result.
As used herein, the terms “comprising,” “having,” and “including” are used in their open, non-limiting sense. The terms “a,” “an,” and “the” are understood to encompass the plural as well as the singular. Thus, the term “a mixture thereof” also relates to “mixtures thereof.”
As used herein, the term “silicon nitride” includes α-Si3N4, β-Si3N4, SiYAlON, SiYON, SiAlON, or combinations thereof.
As used herein, the term “component” includes the ceramic or glass material, a compound, an implant, a device, or similar, that is useful for antipathogenic purposes.
Generally, the ranges provided are meant to include every specific range within, and combination of sub ranges between, the given ranges. Thus, a range from 1-5, includes specifically 1, 2, 3, 4 and 5, as well as sub ranges such as 2-5, 3-5, 2-3, 2-4, 1-4, etc. All ranges and values disclosed herein are inclusive and combinable. For examples, any value or point described herein that falls within a range described herein can serve as a minimum or maximum value to derive a sub-range, etc. Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients and/or reaction conditions may be modified in all instances by the term “about,” meaning within +/−5% of the indicated number.
Additional features and advantages of the disclosure will be set forth in the description which follows, and in part will be obvious from the description, or can be learned by practice of the herein disclosed principles. The features and advantages of the disclosure can be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. These and other features of the disclosure will become more fully apparent from the following description and appended claims or can be learned by the practice of the principles set forth herein.
Aspects of the present disclosure relates to systems and methods for manufacturing a component, and particularly to manufacturing a component using hot-isostatic pressing with non-adiabatic cooling. Under the high temperature and pressure conditions of hot isostatic pressing, the intergranular phase of the component is a liquid. In some examples, the intergranular phase liquid may have a consistency similar to melted container glass. Without being bound by theory, the solubility of nitrogen gas is high at the increased temperature and pressure of hot isostatic pressing; thus, by maintaining a high overpressure during cooling, the ability of nitrogen to precipitate out of the glass due to its decreased solubility is hindered. Also without being bound by theory, higher overpressures held for longer periods of cooling maintain a longer duration of nitrogen dissolution, thus increasing the supersaturation of nitrogen in the finished component. Even if overpressure is released too early, a significant amount of nitrogen may still be mobile within the intergranular phase of the component.
Methods disclosed herein may include gas-pressure hot-isostatic pressing to supersaturate glass-based compositions with nitrogen by using non-adiabatic cooling (i.e. holding the hot-isostatic pressing pressure constant during the cooling cycle). For example, the method may include holding a high and constant pressure of nitrogen in the hot-isostatic pressing operation during the entire cooling cycle. Surprisingly, this maintains the supersaturation of nitrogen within the hot-isostatic pressed material. The excess nitrogen is then available for antipathogenic purposes.
The methods for manufacturing a component disclosed herein advantageously enable the production of components supersaturated with nitrogen to increase the antipathogenic properties of the component. For example, the methods disclosed herein enable the production of antipathogenic components, such as biomedical implants and devices including but not limited to dental implants, spinal implants, joint components, orthopedic implants, pedicle screws, in-dwelling catheters, endotracheal tubes, colonoscopy scopes, and other similar devices and the like.
Alternatively, in some embodiments, the components may be manufactured as fomites, having a high contact surface. Non-limiting examples include materials or surfaces which are likely to carry infection, such as handles, knobs, trays, counters, furniture, levers, bed rails, chairs, moveable lamps, light switches, cellular phone cases, tray tables, small counter surfaces, or other surfaces, masks, cloth, drapes, gowns, and other clothes, or utensils, tools, instruments, fixtures, or the like. One of ordinary skill in the art would recognize other benefits to employing aspects of the instant invention in various industries.
Without being limited to a particular theory, increased nitrogen content within silicon nitride may provide a surface chemistry such that increased ammonia (NH3) is available for the inactivation or lysis of virus, bacteria, or fungi.
Nitrogen elutes faster (within minutes) than silicon because surface silanols are relatively stable. For viruses, it was surprisingly found that silicon nitride may provide for RNA cleavage via alkaline transesterification which leads to loss in genome integrity and virus inactivation. Increasing the nitrogen content in a silicon nitride material ensures that nitrogen is available for the RNA cleavage to take place.
In an embodiment, the antipathogenic component may exhibit elution kinetics that show: (i) a slow but continuous elution of ammonia from the solid state rather than from the usual gas state; (ii) no damage or negative effect to mammalian cells; and (iii) an intelligent elution increasing with decreasing pH.
In step 110, a ceramic or glass material is received within a containment vessel. In some examples, the ceramic or glass material may include but is not limited to silicon nitride, glass ceramics, and/or polycrystalline ceramics. The ceramic or glass material may be in the form of a powder or may be pre-sintered prior to being placed in the containment vessel. The ceramic or glass material may already be formed into the shape of the desired component before being received within the containment vessel. Alternatively, the ceramic or glass material may be a powder when placed in the containment vessel and subsequently formed into the shape of the desired component within the containment vessel.
The ceramic or glass material may contain about 75 to about 99.9 wt. % of silicon nitride powder. For instance, the amount of silicon nitride powder present in the ceramic or glass material may be about 75 to about 80 wt. %, about 80 to about 85 wt. %, about 85 to about 90 wt. %, about 90 to about 95 wt. %; about 95 to about 99 wt. %, or about 100 wt. %, based on the total weight of the ceramic or glass material. The ceramic or glass material may be about 30 to about 99.9 wt. % of the component. For instance, the amount of ceramic or glass material present in the finished component may be about 30 to about 50 wt. %, about 50 to about 75 wt. %, about 75 to about 80 wt. %, about 80 to about 85 wt. %, about 85 to about 90 wt. %, about 90 to about 95 wt. %; about 95 to about 99 wt. %, or about 100 wt. %, based on the total weight of the component.
The method may employ a ceramic or glass material that includes about 25 wt. % or less of an additional powder, based on the total volume of the ceramic or glass material. In some instances, the amount of additional powder present in the ceramic or glass material is about 25 wt. % or less, about 20 wt. % or less, about 18 wt. % or less, about 16 wt. % or less, about 14 wt. % or less, about 12 wt. % or less, about 10 wt. % or less, about 8 wt. % or less, about 6 wt. % or less, about 4 wt. % or less, about 2 wt. % or less, or about 1 wt. % or less. In at least one instance, the ceramic or glass material consists of or consists essentially of silicon nitride powder and impurities. The additional powder may comprise about 0.1 wt. % or more of sodium oxide (Na2O), lithium oxide (Li2O), potassium oxide (K2O) magnesium oxide (MgO), aluminum oxide (Al2O3), yttrium oxide (Y2O3), ytterbium oxide (Yb2O3), lanthanum oxide (La2O3), strontium oxide (SrO), calcium oxide (CaO), silicon dioxide (SiO2), zirconium oxide (ZrO2), boron trioxide (B2O3), phosphorus pentoxide (P2O5) or combinations thereof.
In step 120, heat and isostatic pressure are simultaneously applied to the ceramic or glass material within the containment vessel. The ceramic or glass material is heated to a first temperature and the pressure is increased to a first pressure. The temperature and pressure may be applied uniformly within the containment vessel. The containment vessel may be configured to operate at high temperatures and pressures during operation. In an embodiment, the containment vessel may use pressurizing nitrogen (N2) gas to increase the pressure within the containment vessel.
In some embodiments, the first temperature may be about 1400° C. to about 1800° C. For example, the first temperature may be about 1400° C. to about 1450° C., about 1450° C. to about 1500° C., about 1500° C. to about 1550° C., about 1550° C. to about 1600° C., about 1600° C. to about 1650° C., about 1650° C. to about 1700° C., about 1700° C. to about 1750° C., or about 1750° C. to about 1800° C. In some examples, the first temperature may be at least 1600° C., at least 1700° C., or at least 1800° C. In one embodiment, the first temperature is about 1800° C. The containment vessel may be heated at a rate of about 10° C./minute until the first temperature is reached.
In an embodiment, the first pressure may be about 100 MPa to about 300 MPa. For example, the first pressure may be about 100 MPa to about 150 MPa, about 150 MPa to about 200 MPa, about 200 MPa to about 250 MPa, or about 250 MPa to about 300 MPa. In some examples, the first pressure may be at least 100 MPa, at least 150 MPa, at least 200 MPa, at least 250 MPa, or at least 300 MPa. In one embodiment, the first pressure is about 150 MPa. In another embodiment, the pressure increases by about 1.2 MPa per minute.
In step 130, the first temperature and the first pressure are held for a period of time. The period of time may range from about 0.5 hours to about 2 hours. For example, the first temperature and first pressure may be maintained within the containment vessel for at least about 0.5 hours, at least about 1 hour, at least about 1.5 hours, or at least about 2 hours. In one embodiment, the first temperature and first pressure may be maintained within the containment vessel for about 1 hour.
In step 140, the ceramic or glass material is cooled within the containment vessel to a second temperature while maintaining the first pressure (e.g. non-adiabatic cooling). The second temperature may be any temperature cooler than the first temperature. For example, the second temperature may be about 30° C. to about 50° C., about 50° C. to about 100° C., about 70° C. to about 120° C., or about 100° C. to about 150° C. In some examples, the second temperature may be less than about 100° C., less than about 50° C., or less than about 30° C. Without being limited to any one theory, the non-adiabatic cooling under the pressure of nitrogen gas allows for the ceramic or glass material to be supersaturated with nitrogen. In some embodiments, the ceramic or glass material may be cooled at a rate of between about 5° C. to about 10° C.
Supersaturation is dependent upon the composition of the material. The ceramic or glass material may be supersaturated in a range of 10 wt. % to 15 wt. %. In an embodiment, the ceramic or glass material includes at least about 1 wt. %, at least about 2 wt. %, at least about 3 wt. %, at least about 4 wt. %, at least about 5 wt. %, at least about 6 wt. %, at least about 7 wt. %, at least about 8 wt. %, at least about 9 wt. %, at least about 10 wt. %, at least about 11 wt. %, at least about 12 wt. %, at least about 13 wt. %, at least about 14 wt. %, or at least about 15 wt. % more nitrogen content than the ceramic or glass material that is not cooled non-adiabatically.
In step 150, the containment vessel is depressurized to a second pressure. In an embodiment, the second pressure may be about 0.1 MPa to about 5 MPa. For example, the second pressure may be about 0.1 MPa to about 0.5 MPa, about 1 MPa to about 2 MPa, about 2 MPa to about 3 MPa, about 3 MPa to about 4 MPa, or about 4 MPa to about 5 MPa. In one embodiment, the second pressure is about atmospheric pressure. In another embodiment, the pressure may be lowered at a rate of between about 2 MPa to about 3 MPa.
In some cases, method 100 may further include removing the component from the containment vessel. After the ceramic or glass material is cooled non-adiabatically and then the pressure is reduced, the component made of the ceramic or glass material supersaturated in nitrogen may be removed from the containment vessel.
According to a second aspect, provided is a component (e.g., an implant) comprising a silicon nitride supersaturated in nitrogen that is produced by a method including receiving the ceramic or glass material within a containment vessel; simultaneously heating and applying isostatic pressure to the ceramic or glass material within the containment vessel to a first temperature and a first pressure using pressurizing nitrogen gas; holding the first temperature and the first pressure for a period of time; cooling the ceramic or glass material within the containment vessel to a second temperature while maintaining the first pressure; and depressurizing the containment vessel to a second pressure. In some instances, the implant may be manufactured using one or more features of method 100, which is discussed above.
The component typically includes about 30 wt. % to about 100 wt. % ceramic or glass material. For instance, the amount of ceramic or glass material present in the finished component may be about 30 to about 50 wt. %, about 50 to about 75 wt. %, about 75 to about 80 wt. %, about 80 to about 85 wt. %, about 85 to about 90 wt. %, about 90 to about 95 wt. %; about 95 to about 99 wt. %, or about 100 wt. %, based on the total weight of the component. In various embodiments, the ceramic or glass material is silicon nitride, a glass ceramic, and/or a polycrystalline ceramic. The ceramic or glass material may contain about 75 to about 99.9 wt. % of silicon nitride powder. For instance, the amount of silicon nitride powder present in the ceramic or glass material may be about 75 to about 80 wt. %, about 80 to about 85 wt. %, about 85 to about 90 wt. %, about 90 to about 95 wt. %; about 95 to about 99 wt. %, or about 100 wt. %, based on the total weight of the ceramic or glass material. In an embodiment, the ceramic or glass material includes at least about 1 wt. %, at least about 2 wt. %, at least about 3 wt. %, at least about 4 wt. %, at least about 5 wt. %, at least about 6 wt. %, at least about 7 wt. %, at least about 8 wt. %, at least about 9 wt. %, at least about 10 wt. %, at least about 11 wt. %, at least about 12 wt. %, at least about 13 wt. %, at least about 14 wt. %, or at least about 15 wt. % more nitrogen content than the ceramic or glass material that is not cooled non-adiabatically.
Preferably, the component (e.g., an implant) is antipathogenic. For example, the component may inhibit the proliferation of at least one of bacteria, fungi, and viruses. In some examples, the bacteria may be S. epidermis. Additionally, and/or alternatively, the component may be configured to be an implant that enhances osteoblast cell proliferation. In at least one embodiment, the osteoblast cell proliferation increases on the implant as compared to an implant without the silicon nitride powder. The component may have a surface chemistry that accelerates bone repair. In some embodiments, the component (e.g., an implant) releases silicic acid and nitrogen from the surface of the component, which enhances the osteogenic activity of osteosarcoma and mesenchymal cells both at the initial stages of cell differentiation and during subsequent bony apatite deposition. Without being limited to any particular theory, the silicon nitride powder may stimulate the synthesis by osteoblasts of high-quality bone tissue, the former favoring bone matrix mineralization and the latter enhancing cell proliferation and formation of bone matrix. In addition, the component may possess a surface chemistry that is biocompatible and provides a number of biomedical applications including concurrent osteogenesis, osteoinduction, osteoconduction, and bacteriostasis.
The component may be in the form of an implant or device, which may be implanted in a patient's body in an area contacting or near bone. Non-limiting examples of implants include an intervertebral spinal spacers or cages, bone screws, orthopedic plates, and other fixation devices, articulation devices in the spine, hip, knee, shoulder, ankle, and phalanges, implants for facial or other reconstructive plastic surgery, middle ear implants, dental devices, pedicle screws, in-dwelling catheters, endotracheal tubes, colonoscopy scopes, and other similar devices and the like.
It was hypothesized that holding pressure during cooling after hot isostatic pressing (HIP) could be used as a means to supersaturate Si3N4's secondary silicon yttrium aluminum oxynitride (SiYAlON) glassy phase with excess nitrogen. It was further hypothesized that the excess nitrogen stored in the glass would cause accelerated release of ammonia into the physiologic medium as the SiYAlON was hydrolyzed, in turn enhancing the observed antimicrobial properties of the material. Four lots of silicon nitride test discs were processed from the same standard powder lot and subjected to different HIP cycles: (1) no HIP/sinter only at one atmosphere, (2) standard HIP with adiabatic (simultaneous release of pressure & temperature) cooldown, (3) 10 ksi hold during HIP cooldown, and (4) 25 ksi hold during HIP cooldown. Discs were subjected to a battery of materials characterization techniques and in vitro challenges with a biofilm-forming strain of S. epidermidis and pre-osteoblast KUSA-A1 mesenchymal stem cells in order to assess what effects, if any, the alteration of the HIP cycle had on the material's properties and biologic response.
It was also hypothesized that excess nitrogen sequestered into the minority SIYAlON glassy phase by controlling HIP pressure during cooling could (1) prevent or mitigate the formation of strength-limiting pores during HIP cooldown and (2) create a residual stress, measurable as a β-Si3N4 lattice strain, following processing. Mitigation of the gas-formed pore flaw population and the presence of a residual stress could act in tandem to inhibit crack propagation in the material leading to an observable increase in flexural strength. Flexural bar lots were made using adiabatic HIP cooling and 25 ksi hold during HIP cooling. Following flexural testing, the results from these lots were analyzed and compared to determine effects upon the material's strength distribution. Discs processed with differing HIP conditions as described above were subjected to X-ray diffraction. Peak positions of four principal peaks were compared for representative samples to assess lattice strain.
Sample sizes for bacterial experiments were n=3 (bacteria) and n=variable per analysis technique (KUSA-A1 experiments) per condition and timepoint per established protocols. Sample sizes for flexural strength tests were n≥30 per ASTM C1161-186.
Null Hypothesis 1—Change in Antibacterial Properties: Controlling pressure during HIP cooldown will not modify Si3N4's antibacterial properties such that CFU counts for a 25 ksi HIP cool sample would be lower than a sinter only or adiabatically cooled Si3N4 tested in parallel using SINTX's standard bacterial biofilm assay with a biofilm forming strain of Staphylococcus epidermidis (S. epidermidis). This hypothesis will be rejected if the CFU counts at 24 and 48 hour time points are lower with statistically significant p-values via a Student's t-test (2-tail, heteroscedastic) for the 25 ksi HIP cooldown material relative to the adiabatic cool material and the sinter only material.
Null Hypothesis 2—Strength Improvement: Holding pressure constant during HIP cooldown will not lead to improvement in the material's flexural strength. This hypothesis will be rejected if the average three point bending strength (per 940006) of the 25 ksi HIP cool material improves and comparison of the adiabatic cool test group and 25 ksi test group strength distributions yield a p-value less than 0.05 via a Student's t-test (2-tail, heteroscedastic, 95% confidence).
Null Hypothesis 3—Lattice Strain: Holding pressure constant during HIP cooldown will not impart residual lattice strain. This hypothesis will be rejected if X-ray diffraction peak shifts indicate a progressive increase in β-Si3N4 lattice strain (measured as a change in d-spacing) that correlates with magnitude of pressure applied during HIP cooldown.
The silicon nitride powder lot used in this work had a nominal composition (mass percent) of 0.75% TiO2 (New Brunswick, N.J. USA), 3.97% Al2O3 (UFX-MAR, Baikowski-Malakoff, Malakoff, Tex. USA), 5.96% Y203 (Triebacher Industrie AG, Althofen, Austria), and the balance as Si3N4 (Ube SN-E10, Ube, Japan). Briefly, this material was prepared by batching an aqueous slurry containing common commercially available organic dispersants and binders, milling the slurry in a circulating attrition mill (Q6, Union Process, Akron, Ohio USA) to deagglomerate the slurry, and then atomizing and drying the slurry using a spray dryer (NIRO® SD-6.3-N, GEA, Copenhagen, Denmark). Following spray drying, a common press lubricant was mixed into the powder at very low concentration (<1% by mass), the powder was then sieved to remove coarse agglomerates, and the powder was finally held in a controlled humidity chamber (Lunaire CEO 932, Tenney Environmental, New Columbia, Pa. USA) for at least one week to allow for stabilization of its residual moisture content.
All test discs were pressed to a target pressure of 300 MPa using a uniaxial hydraulic press (Carver, Wabash, Ind. USA) and a laboratory KBr pellet (∅12.7 mmט1 mm thick) die (VWR, Radnor, Pa. USA) per PARs 2096, 2097, 2098, & 2099 and co-fired using identical parameters except for their respective HIP cycles. The common firing steps were (1) binder removal in air up to 500° C. (ThermalTek, Concord, N.C. USA), (2) Binder removal and pre-sinter in 2 psi of nitrogen with a two hour hold at 1600° C. in a batch furnace (Centorr Vacuum Industries, Nashua, N.H. USA), and (3) sintering at 1710° C. for three hours in a continuous belt furnace (Centorr Vacuum Industries, Nashua, N.H. USA) under flood nitrogen (one atmosphere) conditions. The HIP (Quintus Technologies, LLC, Columbus, Ohio USA) cycles employed are detailed in Table 1.
Following thermal processing, discs were subjected to CO2 blasting, ultrasonic cleaning, and clean firing (700° C. in air for 30 minutes) to ensure their surfaces would be representative of processed implants.
Poly(ether ether ketone) (PEEK) discs were also produced for use as controls in bacterial biofilm assays. PEEK rod stock (∅12.7 mm) (ASTM D6262, Ketron® PEEK 1000, McMaster-Carr, Santa Fe Springs, Calif.) was machined by a commercial machining house into discs with a 1 mm thickness.
Flexural Bar Production: A control group of flexural bars processed with the standard adiabatic cool HIP cycle were produced. These test bars were dry isostatically pressed (310 MPa) in an elastomer mold to form square cross-section bar stock ˜21 mm×21 mm. The pressed bar stock was subjected to (1) binder removal and pre-sinter (Batch Furnace) by conducting a series of low temperature ramps and holds under vacuum up to 700° C. to volatilize organic constituents and then ramping to 1600° C. in 2 psi of nitrogen and holding for two hours, (2) sintering at 1710° C. for three hours (Belt Furnace) in flood nitrogen (one atmosphere) conditions, and (3) HIP cycle −1690° C., 2 hr exposure in 22 ksi N2 with adiabatic cooldown. Following HIP, stock pieces were subjected to Archimedean density testing (n=3), then shipped to a commercial grinding house for processing into ASTM C1161-187 configuration B test bars (3 mm×4 mm cross-section×45 mm length). Once the ground bars were received back, their tensile faces were polished using a lapping machine (Lapmaster 15, Lapmaster, Mt. Prospect, Ill. USA).
The experimental flexural bar group was processed. The processing for this group was identical in all respects to that of the control group with the exception of the HIP cycle. This cycle consists of the same ramp and hold at 1690° for 2 hours at 22 ksi N2. Instead of adiabatic cooling, the pressure ramps to 25 ksi N2 during cooldown and holds until the vessel temperature is below 300° C. Post-HIP processing and testing were identical to what was performed for the control group.
Dimensional density measurements were carried out on six test discs. Diametral measurements were used to calculate linear shrinkage (SL) from six test discs.
Cross-sectioned samples were prepared by mounting disc samples in epoxy resin (EpoThin, Buehler, Lake Bluff, Ill.), grinding several mm deep into the disc using a 400 grit diamond-embedded wheel on a surface grinder (ACC 12-24 DX Grind-X, Okamoto Corp., Vernon Hills, Ill. USA), then lapping using successively finer diamond grits (Engis, Wheeling, Ill. USA) against cast iron plates and culminating with a chemical mechanical polishing (CMP) process using colloidal silica (Engis) against a polishing pad (Suba IV, Engis).
Evaluations of Surface Morphology and Microstructure: As-fired surfaces were evaluated using a Confocal Laser Scanning Microscope (CLSM) (LEXT OLS5000, Olympus, Japan) to quantify their roughness parameters. As-fired and polished cross-sections prepared as described above were evaluated using a field emission gun scanning electron microscope (FEG-SEM) (Quanta, FEI, Hillsboro, Oreg. USA) equipped with an energy dispersive X-ray spectrometer (EDS) (EDAX, Mahwah, N.J. USA). Samples were sputter coated (PECS 1, Gatan, Pleasanton, Calif. USA) with a thin (˜3 nm) layer of gold-palladium alloy to form a conducting path necessary for electron imaging.
X-Ray Diffraction: A diffractometer (PANalytical X-Pert, Malvern, United Kingdom) was used to perform X-ray diffraction on disc samples from each lot using a scan range of 20° to 70° 2θ with a step size of 0.02° and a time per step of 0.75 s. A Cu K-Alpha source (λ=1.540598 Å) was used with a brass mask (10 mm), a divergence slit (½°), an anti-scatter slit (¼°), and a receiving slit (⅛°).
Contact Angle Measurements: Droplets (25 μL) of deionized water (17.5 MΩ cm resistivity, 75011, Myron L Company, Carlsbad, Calif.) were deposited (VWR Signature Variable Volume Pipette, VWR, Radnor, Pa.) onto sample surfaces (n=3 samples per condition, two measurements per sample) and measured using an optical comparator (2600 Series, S-T Industries, St. James, Minn.) via a procedure established in previous work.
Bacterial Biofilm Assay: An in vitro S. epidermidis (ATCC® 14990™) bacterial biofilm assay was performed per a previously established procedure using n=3 discs per condition. Briefly, Samples were immersed in wells containing 105 cells/mL in a nutrient broth comprised of diluted human plasma and glucose in phosphate buffered saline (PBS). Following exposure (time points of 24 & 48 hours), samples were removed from the broth, rinsed with PBS to remove non-adherent bacteria, and vortexed to separate adherent bacteria from the sample surfaces. Adherent bacteria suspensions were serially diluted and plated onto Petrifilm™ (6400/6406/6442 Aerobic Count Plates, The 3M Company, Minneapolis, Minn.), and colony forming units (CFUs) were counted after a 24 hour incubation period. Differences in CFUs normalized by specimen surface area for each condition were evaluated for statistical significance using a Student's t-test (2-tail, heteroscedastic, 95% confidence) at each time point.
Osteoconductivity Testing: Samples were exposed to KUSA-A1 stem cells in vitro via a previously established procedure for a period of 28 days. Samples were subjected to staining with Alizarin red and subsequent measurement of medium optical density (OD) at 450 nm (n=5), volumetric measurement of deposited mineralized bone tissue (n=10) via confocal scanning laser microscopy (CSLM) (Keyence, Japan), Raman imaging to qualitatively assess formation of bone mineral and soft matrix, and high resolution Raman spectroscopy (n=8) to assess inorganic to organic ratio of the deposited boney tissue, hydroxyapatite (HAp) crystallinity, and ratio of HAp to tricalcium phosphate (TCP).
Flexural Strength: Testing was carried out per 940006—Flexural Strength Test Procedure, which conforms to ASTM C1161-187 (configuration B), on test bars (n=36 bars per lot). Briefly, this is a 3-point bend test with a 40 mm span performed on a universal mechanical test frame (5567, Instron, Norwood, Mass. USA) using a crosshead speed of 0.50 mm/min. Obtained data for each lot were compared using a Student's t-test (2-tail, heteroscedastic, 95% confidence). Further analyses were carried out per ASTM C12399 to obtain Weibull parameters for describing the failure distributions of both material lots. Graphical construction of the Weibull plot was carried out per sections 8.8 and 8.9 of ASTM C1239, and unbiasing of the obtained Weibull moduli were performed per section 9.2 of ASTM C1239. A limited fractographic analysis was conducted using a visible light stereomicroscope (SZX9, Olympus, Japan) for selected low strength (<800 MPa) samples.
Lattice Strain Assessment: Diffraction data were analyzed using commercially available phase analysis software (MATCH!, Crystal Impact, Bonn, Germany) to determine peak locations for [110], [210], [200], and [101] reflections in β-Si3N4's pattern. These are the four principal reflections in the referenced standard pattern (JCPDS-ICDD No. 33-1160) for this material.
Test Disc Characterization: Table 2 shows the dimensional density and linear shrinkage for samples subjected to the various HIP conditions. It can be concluded from the data in Table 2 that the HIPed samples were likely modestly denser than the Sinter Only samples. Further, it appears qualitatively that increasing HIP cooldown pressures yield a modest increase in density.
Optical images and corresponding intensity maps captured using CLSM are shown in
Low magnification secondary electron images in
At higher magnification in
In the back-scatter mode, contrasting by atomic number/density is obtained. This allows for easy visualization of phases with significantly different densities. High density materials reflect more electrons and therefore show up brighter while lower density phases show up darker. In all samples imaged in
All four sample groups shown in
Water contact angles are shown in Table 4. The HIP samples all exhibited very similar water contact angles. The sinter only sample exhibited a significantly larger contact angle. This could have been due to increased surface roughness and porosity relative to the HIP samples. Additionally, the sinter only samples had been stored for a long period while the HIP samples were being processed. As such, there may have been more adventitious carbon buildup on the sinter only samples that was not adequately cleaned away prior to measurement.
S. epidermidis in vitro Bacterial Biofilm Assay: The data charted in
KUSA-A1 MSC Assay 1—Alizarin Red & Volumetric Bone Tissue Deposition:
KUSA-A1 MSC Assay 2—Raman Imaging: Raman imaging data presented in
KUSA-A1 MSC Assay 3—High Resolution Raman Spectroscopy: Data in
Except for the 10 ksi sample group, all groups exhibited similar behavior in terms of amounts and quality of bone tissue produced. The cells exposed to the 25 ksi sample group did appear to secrete more extracellular polymer relative to the others, but this is not necessarily deleterious. The cells on the 10 ksi samples produced the least extracellular polymer, which in turn was less mature and mineralized to a lesser extent than the bone tissue from the other groups. Even though these observed differences were statistically significant, differentiation was still well within an order of magnitude in all cases. Thus, it is doubtful that these moderate differences observed in vitro would translate to significant changes in behavior in vivo.
Flexural Strength: Data presented in Table 5 show the density and average strength of silicon nitride produced using the 25 ksi HIP cooldown cycle.
Measured density is equivalent to material produced using the standard production adiabatic cooling cycle. The weakest bars in the adiabatic cool lot failed at strengths between 650 and 700 MPa, indicating defect-driven behavior. Notably, the weakest bar in the 25 ksi cool lot failed at 1000 MPa, which was the average strength for the adiabatic cool lot. The strongest bar from the adiabatic cool lot failed at 1170 MPa, while the strongest bar from the experimental lot failed at 1420 MPa. Average flexural strength for the experimental lot is increased by about 250 MPa, and a Student's t-test (2-tail, heteroscedastic) shows that the differences between the two flexural experiment sample sets are statistically significant. The differences between the lot average, maximum, and minimum strength indicate a shift on the order of 200-300 MPa in the entire strength distribution between the two groups. Generally, defect eliminations tend remove low strength tails from strength distributions without affecting the strength values at the less defect-affected high end of the distribution. So, the complete distribution shift could be indicative of either removal/size reduction of an entire flaw population or some other fundamental material change occurring.
Brittle material failure distributions tend to better conform to the Weibull distribution than the normal distribution. Therefore, the failure data for both lots are presented as a Weibull probability plot in
Images of fracture origins for specimens that failed below 800 MPa are presented in
Lattice strain from XRD peak shift: Charts showing the peak positions for the four primary reflections for β-Si3N4 are presented in
Eqn. 1 is Bragg's Law, where n is the order of reflection, λ is the wavelength of the incident radiation, d is the interplanar spacing within the crystal, and θ is the angle of incidence.
Since nλ is constant for a given reflection and radiation source, and sine increases as θ increases up to θ=90°, a peak shift to a higher diffraction angle in the observed range corresponds to a narrower d-spacing between atomic planes of that peak's orientation. Observation of the same trend in peak shift with very similar magnitudes of diffraction angle increase for all principal peaks is consistent with β-phase crystallites in the HIP samples being in a state of residual isotropic compressive strain whose magnitude increases as applied pressure during HIP cooldown increases. This is also consistent with a higher overpressure causing a higher degree of nitrogen supersaturation in the continuous glass phase resulting in (1) closure of volumetric defects (2) prevention of pore formation from N2 evolution, and (3) residual strain volumetric constraint.
Controlling the cooldown phase of the HIP cycle has significant impact on the resulting Si3N4 material's microstructure and properties. Holding the gas pressure constant during cooling mitigates evolution of nitrogen at intermediate temperatures where the solubility of nitrogen in the glass decreases but mobility is still relatively high. This reduces the size of pores that form during the cooldown phase of the HIP process. Holding the pressure constant at a value greater than the process pressure appears to greatly reduce the size and frequency of pores in the microstructure. Decreasing the size and frequency of these pore defects leads to a direct improvement in strength as expected from well-established fracture mechanics science. Further, XRD data show that a residual stress state exists in the material that is proportional to the magnitude to the pressure applied during HIP cooldown. This residual stress state could contribute to the large observed improvement in strength that accompanies processing with a high pressure hold during HIP cooldown.
No deleterious effects were observed for bacterial biofilm assay performance or osteoconductivity test performance for the material subjected to the 25 ksi HIP cooldown cycle, and the strength increase that could be realized is substantial. The experiments that showed a large improvement in strength and reliability should be repeated as part a verification effort component of a formal controlled process change to introduce the 25 ksi cooldown HIP cycle into MC2 processing.
Having described several embodiments, it will be recognized by those skilled in the art that various modifications, alternative constructions, and equivalents may be used without departing from the spirit of the invention. Additionally, a number of well-known processes and elements have not been described in order to avoid unnecessarily obscuring the present invention. Accordingly, the above description should not be taken as limiting the scope of the invention.
Those skilled in the art will appreciate that the presently disclosed embodiments teach by way of example and not by limitation. Therefore, the matter contained in the above description or shown in the accompanying drawings should be interpreted as illustrative and not in a limiting sense. The following claims are intended to cover all generic and specific features described herein, as well as all statements of the scope of the present method and system, which, as a matter of language, might be said to fall therebetween.
This application claims priority to U.S. Provisional Application No. 63/104,852 filed Oct. 23, 2020, the entirety of which is incorporated by reference herein.
| Number | Date | Country | |
|---|---|---|---|
| 63104852 | Oct 2020 | US |
