ORTHOPAEDIC IMPLANT

Abstract

An orthopaedic implant comprising a titanium substrate having silver deposited thereon, wherein the silver is operable to be eluted at a rate of at least 0.25 μg/cm2 24 h-1, for at least 14 consecutive days, in use. The invention also extends to a method of producing an orthopaedic implant and use of the same.

Claims

1. An orthopaedic implant comprising a titanium substrate having bioactive metal deposited thereon and having a polymer coating thereon, the polymer coating being applied to the titanium substrate having bioactive metal deposited thereon at a rate of between 10 mm/min and 1000 mm/min.

2. The orthopaedic implant of claim 1, wherein the polymer coating is operable to allow elution of the bioactive metal into the body at a rate of at least 0.25 μg/cm.sup.2 24 h.sup.-1, in use.

3. The orthopaedic implant of claim 1, further comprising a titanium substrate having bioactive metal deposited thereon at an amount of at least 10 μg/cm.sup.2.

4. The orthopaedic implant of claim 1, wherein the bioactive metal is operable to be eluted at a rate of at least 0.25 μg/cm.sup.2 24 h.sup.-1, for at least 14 consecutive days, in use, and wherein the titanium substrate having the bioactive metal deposited thereon is obtainable by contacting the titanium substrate with an 7 to 13M solution of a group I or group II metal hydroxide to thereby passivate the titanium substrate, then contacting the passivated titanium substrate so obtained with a metal material.

5. The orthopaedic implant of claim 1, wherein the bioactive metal is selected from one or more of the following: silver, gold, copper, tin, antimony, platinum, gallium, palladium, and zinc.

6. The orthopaedic implant of claim 1, wherein the orthopaedic implant comprises at least one anchor point, operable to allow the implant to be anchored in place, in use.

7. The orthopaedic implant of claim 6, wherein the at least one anchor point includes protecting means operable to protect bioactive material deposited thereon during anchoring of the implant.

8. The orthopaedic implant of claim 1, wherein the orthopaedic implant includes one or more surface features operable to reduce the contact surface between the implant and the area to which the implant is inserted, in use, wherein the surface feature includes one of ribs, channels, or recesses.

9. The orthopaedic implant of claim 1, wherein the implant comprises an orthopaedic joint implant selected from one of a shoulder implant, a hip implant, a knee implant, a wrist implant, an interphalangeal implant, a partial or carpal joint implant, an ankle implant, an elbow implant, a spinal implant, an orthopaedic nail, a femoral nail, a tibial nail, an orthopaedic bone plate, a fastener, a screw, a wire, or a pin.

10. A method of forming the orthopaedic implant of claim 1, comprising applying a polymeric coating to a titanium substrate having silver deposited thereon at a rate between 10 mm/min and 1000 mm/min.

11. The method of claim 10, wherein the polymeric coating is applied to the orthopaedic implant by dip coating comprising the steps of: (i) immersing the orthopaedic implant in a coating solution comprising a polymeric material and a solvent; (ii) withdrawing the orthopaedic implant from the coating solution at the rate of between 10 mm/min and 1000 mm/min to form a wet layer; and (iii) curing the polymeric coating.

12. The method of claim 10, further comprising contacting the titanium substrate with a 7 to 13M solution of a group I or group II metal hydroxide to thereby passivate the titanium substrate, then contacting the passivated titanium substrate so obtained with a silver material.

13. The method of claim 10, further comprising contacting the titanium substrate having silver deposited thereon with a blackening reducing agent.

14. The method of claim 13, wherein the blackening reducing agent comprises sodium sulphide.

15. The method of claim 13, wherein the blackening reducing agent is selected from one or more of the following: polyvinylpyrrolidone, poly(vinyl alcohol), poly(ethylene glycol), sodium chloride, sodium sulphide, alkaline glucose, sodium citrate, ascorbate, poly (ethylene glycol)-block, sodium borohydride.

16. The method of claim 10, wherein the titanium substrate comprises silver ions and/or silver nanoparticles.

17. An orthopaedic implant comprising a titanium substrate having silver deposited thereon, wherein the titanium substrate having silver deposited thereon is contacted with a blackening reducing agent, and wherein the silver is operable to be eluted at a rate of at least 0.25 μg/cm.sup.2 24 h.sup.-1, for at least 14 consecutive days, in use.

18. The orthopaedic implant of claim 17, wherein the titanium substrate comprises silver ions and/or silver nanoparticles.

19. The orthopaedic implant of claim 17, wherein the blackening reducing agent comprises a sodium sulphide.

20. The orthopaedic implant of claim 17, further comprising a polymer coating thereon, the polymer coating being applied to the titanium substrate having silver deposited thereon at a rate of between 10 mm/min and 1000 mm/min.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0208] For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the following experimental data and figures, in which.

[0209] FIG. 1 shows a graph of experimental data relating to alkali passivation of titanium coupons carried out at different molarities;

[0210] FIG. 2 shows a graph of experimental data relating to alkali passivation of titanium coupons carried out at differing temperatures;

[0211] FIG. 3 shows a bar chart of experimental data relating to silver titanate treated parts subject to treatment with various reagents;

[0212] FIG. 4 shows a further bar chart of experimental data relating to silver titanate treated parts subject to treatment with various reagents;

[0213] FIG. 5 shows a bar chart of experimental data relating to silver titanate treated parts subject to treatment with sodium sulphide;

[0214] FIG. 6 shows a bar chart of experimental data relating to immersing silver titanate treated parts in 4 g/l sodium chloride;

[0215] FIG. 7 shows a bar chart of experimental data relating to concentration of silver ions in the boundary layer required to kill each of S. aureus or eMRSA;

[0216] FIG. 8 shows a bar chart of experimental data relating to concentration of silver ions in the boundary layer required to kill each of S. aureus or eMRSA;

[0217] FIG. 9 shows a graph of experimental data relating to the rate of elution of silver ions from nails having polymeric coatings thereon;

[0218] FIG. 10 shows a graph of experimental data relating to the rate of elution of silver ions from nails having polymeric coatings thereon;

[0219] FIG. 11 shows a graph of experimental data relating to the rate of elution of silver ions from nails having polymeric coatings thereon;

[0220] FIG. 12 shows a graph of experimental data relating to the rate of elution of silver ions from nails having polymeric coatings thereon;

[0221] FIG. 13 shows a graph of experimental data relating to the rate of elution of silver ions from nails having polymeric coatings thereon;

[0222] FIG. 14 shows a graph of experimental data relating to the rate of elution of silver ions from nails having polymeric coatings thereon;

[0223] FIG. 15A shows a perspective view of a part of an orthopaedic implant having apertures therethrough;

[0224] FIG. 15B shows a perspective view of a part of an orthopaedic implant having apertures therethrough;

[0225] FIG. 16A shows a perspective view of a part of an orthopaedic implant having surface features thereon;

[0226] FIG. 16B shows a cross sectional view through the orthopaedic implant shown in FIG. 16a;

[0227] FIG. 17 shows a perspective view of an end of an orthopaedic implant having surface features thereon; and

[0228] FIG. 18 shows a perspective view of an end of an orthopaedic implant having surface features thereon.

DETAILED DESCRIPTION

EXAMPLES

[0229] Cylindrical coupons in two sizes (8.5 mm diameter×40 mm long) and (2 mm diameter×85 mm long) made from implant grade titanium-64 alloy were manufactured for the purpose of identifying a set of process conditions that could be transferrable to the final product such as, for example, an intramedullary nail with typical dimensions (i.e., 10 mm diameter×30 cm long). The surface finish of the coupons was also carefully controlled and resembled the final product (i.e., a 32 Ra micro-inch produced using either a dry or wet blast process). Surface roughness has a significant impact on the efficiency of the titanate process with a 32 Ra micro-inch grit blasted surface increasing the amount of silver by 33% compared to a machined surface. The coupons were subsequently washed and laser marked for identification.

Alkali Passivation

[0230] The prepared titanium implant is then subjected to alkali passivation by immersing the titanium intramedullary nail in a group I or group II metal hydroxide solution, such as, for example, sodium hydroxide or potassium hydroxide.

[0231] It has been found by the present invention that the alkali passivation step has a significant effect on silver loading. While not wishing to be bound by theory, it is considered that the alkali passivation step may be operable to control the microstructure of the ion exchangeable titanate. In particular, it has been found that the molarity of the metal hydroxide solution and the temperature both have a surprising and unexpected impact on the silver loading achieved.

Molarity of Alkali Agent

[0232] Alkali passivation of a titanium coupon was carried out at three different molarities: 4M, 10M and 18.9M NaOH several times, for differing amounts of time, up to 8 hours. These coupons were each rinsed and then immersed in 0.1M silver nitrate at 60° C. for 1 hour. Silver loading (in μm/cm.sup.2) was then determined using ICP-MS. The standard test method for the characterization of materials for medical devices can be sourced from “Chemical Characterisation of Materials” as per ISO 10993:2005, Part 18, where acid digestion was used to strip silver from the coupon, and Inductively Coupled Mass Spectroscopy (ICP MS) was used as the test method to determine the silver content. ICP MS is a well-established technique and would be well known to a person skilled in the art. Briefly, coupons were immersed in 10 ml of a 2:1 nitric acid:deionised water solution and left overnight. Then, the solutions were mixed by vortex and serially diluted 1,000 × with a 1% solution of nitric acid. The diluted solutions were analysed using ICP MS to quantify the silver content under the following conditions: instrument—Agilent 8800 ICP-MS triple quad; autosampler—ASX-500 series; sample introduction—peri pump; nebuliser—micro mist; lens type—x; scan—single quad; plasma mode—general purpose; acquisition mode—spectrum; spectrum mode options—Q2 peak patterns 3 points, 3 reps, 100 sweeps/rep; elements—Rh (IS) (mass 103, int. time 0.3 s), Ag (mass 107, int. time 0.3 s).

[0233] The results are shown in FIG. 1, wherein the silver loading at 10M NaOH is surprisingly and unexpectedly significantly higher than the silver loading at 4M NaOH or 18.9M NaOH.

Temperature of Alkali Passivation Step

[0234] Alkali passivation of the titanium coupons was carried out at 60° C. and at 90° C. several times, for differing amounts of time, up to 8 hours. These parts were then rinsed and immersed in 0.1M silver nitrate at 60° C. for 1 hour. Silver loading (in μm/cm.sup.2) was then determined using ICP-MS.

[0235] The results are shown in FIG. 2, wherein it can clearly be seen that passivation at 90° C. had a significant beneficial effect on the silver loading.

Colour Improvement

[0236] The deposited silver nano particles (AgNP's) are prone to oxidation under ambient conditions, and also when dried in presence of air/oxygen. On long standing, they can also turn black due to the pick-up of impurities, such as oxygen and silver, due to the large surface area of the AgNP's, which exposes the loosely held outermost electrons to these species. Once de-stabilized, it is generally very difficult to re-disperse the AgNP's because of the high surface to volume ratio.

[0237] In order to control the appearance before or after gamma or ETO sterilization, the silver titanate parts can be subjected to chemical stabilisation using either capping agents (polyvinylpyrrolidone, poly(vinyl alcohol), poly(ethylene glycol), or reducing agents (sodium chloride, sodium sulphide, alkaline glucose, sodium citrate, ascorbate, poly (ethylene glycol)-block, sodium borohydride). The reducing agents reduce silver ions in aqueous or non-aqueous solutions to metallic silver, which is followed by agglomeration into oligomeric clusters. The capping agents stabilize particle growth, and protect particles from sedimentation and agglomeration. Alternatively, non-chemical strategies for stabilizing the appearance of silver titanate include heat treatment (typically 280° C. for 2 hours) and UV photochemical reduction.

[0238] In one experiment, silver titanate treated parts were subject to treatment with either 2.5% w/v PVP, 10 k Mwt, 2.5% w/v PVP 40 k Mwt, 0.1 Mol dm.sup.-3 NaCl, and 2.5% w/v alkaline glucose for 1 hour. In the case of glucose treatment, the part turned black after five (5) minutes prior to sterilization. The other treatments produced a lighter grey appearance comparable to the control (i.e., non-chemically treated titanate).

[0239] After gamma sterilization, all parts turned black with the exception of the parts that were treated with 0.1 Mol dm.sup.-3 NaCl sodium chloride for 1 hour. These parts turned dark grey, which could in turn improve the visibility of laser markings for a final product.

[0240] In this first set of experiments, the grit blasted test coupons were subjected to these chemical agents for 30 minutes. Sodium chloride was the only chemical treatment that retarded the black colour from the first set of experiments. However, as shown in FIG. 3, the level of silver dropped by 25% with this reagent.

[0241] In the second experiment, the silver titanate treated test coupons were subject to sodium 0.1M citrate and 0.1M sodium sulphate solutions for 30 minutes. The sodium sulphate treatment was found to retard the dark colour change after gamma sterilization. In addition, the amount of silver lost after this chemical treatment was negligible, as shown in FIG. 4.

[0242] The next set of experiments involved the use of laser marked cylindrical Ti-64 coupons. The coupons were passivated and silver treated, followed by chemical stabilization with 0.1M sodium sulphide treatment for up to 30 minutes. The non-chemically stabilized coupons exhibited a dark grey colour prior to sterilization. The coupon subjected to the chemical stabilisation agent turned a darker grey. In all cases, the laser markings were clearly discernible from the background metal. Post gamma sterilization, the control coupons darkened in colour. However, the coupons treated in sodium sulphide remained dark grey. In all cases, the laser markings were discernible from the base metal.

[0243] Treatment with 0.1M sodium sulphide for five (5) and thirty (30) minutes did not have a significant effect on total silver, as indicated in FIG. 5.

[0244] For comparative purposes, silver titanate laser marked coupons subject to chemical stabilisation with 4 g/L sodium chloride were submitted for gamma sterilization. Prior to sterilization, all parts had a grey appearance and the laser markings could be read from each coupon. Post gamma sterilization, the five (5) and thirty (30) minute sodium chloride treatments produced a lighter shade of grey. However, the laser markings were discernible from the base metal in all cases.

[0245] Increasing the immersion time in 4 g/l sodium chloride resulted in a decrease in silver level from 91 to 48 μg/cm.sup.2, as shown in FIG. 6. Accordingly, the use of sodium sulphide allows the colour to be controlled such that the laser markings are still visible, but without significant loss of silver.

Determination of Elution Profile

[0246] In order to determine the rate of elution of silver ions required to prevent attachment to the surface of a silver coated intramedullary nail in its intended environment (i.e., a bone canal), it is important to know the concentration of silver ions sufficient to keep it free from microbial contamination. In estimating this minimum silver ion elution rate, it was assumed that a small boundary layer around the implant needs to contain sufficient silver ions to kill any bacteria.

[0247] Tests were conducted to find the concentration of silver ions in the boundary layer required to kill each of S. aureus or eMRSA. Silver ions were added to cultures of each of S. aureus or eMRSA at differing solutions of between 0.05 and 5 μg/ml. This data is shown in FIGS. 7 and 8 where each bar represents one sample. Based on this data, a silver concentration of 2.5 μg/cm.sup.2 was selected as at this silver ion concentration, greater than 50% of the experiments had the microbial count reduced to below the detection limit of 0.7 CFU/ml (colony-forming units per ml) at 24 hours. The detection limit corresponds to an approximate 4 log reduction in microbial count. Using this value, we calculate that the silver ions elution rate required to achieve this concentration is 0.25 g/cm2/day. If we assume that the silver is bound up by biological proteins, chlorides and/or cleared daily then this needs to be re-eluted daily suggesting an estimated minimum elution rate of 0.25 g/cm2/day.

Elution Control by Use of a Polymeric Coating

[0248] Alkali passivation of the titanium test coupons was carried out in a 10M sodium hydroxide solution at 90° C. for 12 hours. The parts were then rinsed and immersed in 0.1M silver nitrate at 60° C. for 1 hour. Silver loading (in μg/cm.sup.2) was determined by the method described above to be approximately 105 μg/cm.sup.2. Polymeric coatings were then added to the passivated parts by dip coating.

[0249] In one experiment, the effect of different solvents was investigated. The silver titanate treated test coupons were dip coated in a 3.3% weight/volume (w/v) solution of PURASORB PDL 45 (a poly-D, L-lactide commercially available from Corbion), in several solvents, at a rate of 50 mm/minute. The solvents used were ethyl acetate, methylene chloride and N-methyl-2-pyrrolidone. The rate of elution of silver ions from nails having polymeric coatings thereon was reduced compared to those having no polymeric coating, as shown in FIG. 9. With all three solvents, the elution rate of silver was controlled by the addition of the polymeric coating extending the release phase to approximately two (2) months. In contrast, the non-coated silver titanate nails only eluted silver ions for about one (1) week.

[0250] In a further experiment, silver titanate treated test coupons were dip coated in a 3.3% weight/volume (w/v) solution of PURASORB PDL 45 (a poly-D,L-lactide commercially available from Corbion) in ethyl acetate at differing rates of between 25 and 300 mm/minute. Increasing the dipping speed reduces the rate of elution of silver ions, as shown in FIG. 10. It was also found that the coating thickness was increased when the dip coating speed was increased, as measured using an optical film analyser system (F40 available from Filmetrics Instruments). The elution rate of the polymeric coating applied at 300 mm/min has the potential to release silver over three (3) months.

[0251] In a further experiment, silver titanate treated test coupons were dip coated in a solution of a lower molecular weight polymer (PURASORB PDL-05, a poly-D, L-lactide commercially available from Corbion) in ethyl acetate at concentrations of 5, 10 and 20% w/v and at a rate of 100, 300 or 500 mm/minute. The elution rate of silver decreased when either the polymer concentration was increased from 5 to 30% w/v, or the dip coating speed was increased from 100 to 300 mm/min. This is shown in FIG. 11. The 20% w/v solution dipped at a rate of 500 mm/minute could elute silver for 420 days based on extrapolated elution data at 15 days.

Effect of Polymer Coating on In Vitro Cytotoxicity of Silver Titanate

[0252] In another experiment, the cytotoxicity of silver titanate treated nails dip coated with a poly-D,L-lactide polymer PDL-45 (3.3 wt % dipped at 100 mm/min) commercially available from Corbion) towards osteoblast MC3T3 cells was tested using the WST-1 assay. The results are shown in Table 1 below. Cytotoxic potential is shown with viability below 70%. Test coupons coated with poly-D, L-lactide significantly increased cell viability with no evidence of cytotoxicity. This data suggests that a polymer coating is a viable option for increasing the silver concentration in the titanate nanostructure without increasing the risk of toxicity.

TABLE-US-00002 TABLE 1 MEAN cell viability SD Sodium titanate 117.8  45.4  Silver Titanate 23.3 0.7 silver titanate + 88.9  3.73 polymer coating

Effect of a Controlled Release Coating on In Vivo Bacterial Colonization

[0253] In one experiment, two (2) week rabbit liquid inoculation infection studies were carried out on silver titanate test coupons, loaded at differing dosage levels of 50 μg/cm.sup.2 (study 1) and 100 μg/cm.sup.2 (study 2) to determine whether a controlled release of local antimicrobial agent prevented bacterial colonization of the implant. This localized tibial osteomyelitis model provides a longitudinal assessment of early post-operative implant infections involving Staphylococcus aureus and an indication of the clinical rate of infection. The silver titanate treated parts were dip coated with differing polymeric coatings. The results are shown in Table 2 below. The in vitro elution rate of coated and polymer coated silver titanate treated pins of the two rabbit studies is shown in FIG. 12.

[0254] Pins dosed at 50 μg/cm.sup.2 without a polymer coating did not have any impact on reducing bacterial colonization, and had a bacterial colonization rate greater than the control pin (passivated titanium). Increasing the dosage of silver from 50 to 100 μg/cm.sup.2 without the polymer coating reduced the bacterial colonization rate to 71.4%. Applying a dip coated polymer (coating 1; PURASORB PDL-02, a poly-D, L-lactide commercially available from Corbion) reduced the bacterial colonization rate to 43%. Pins dosed at 100 μg/cm.sup.2 were also dip coated in PURASORB PDL-45 polymer (a poly-D, L-lactide commercially available from Corbion) at a dipping speed of 80 mm/minute. The implants coated at this dipping speed had a colonization rate of 64%.

[0255] Coating 1, which exhibited the slowest elution rate, produced the lowest rate of bacterial colonization rate. Coating 2, which produced a faster elution rate, produced a higher rate of bacterial colonization rate. The non-coated pins exhibited the highest rate of bacterial colonization rate.

TABLE-US-00003 TABLE 2 Time- Inocu- Colonization Colonization point lation Rate Rate (Silver Formulation Study (weeks) Dosage (Control) Group) Silver 1 2 10.sup.5 cfu 6/7 (86%) 5/7 (71.4%) Titanate (600 μl) (100 μg/cm.sup.2) Silver 1 2 10.sup.5 cfu 6/7 (86%)  7/7 (100%) Titanate (600 μl) (50 μg/cm.sup.2) Silver 1 2 10.sup.5 cfu 6/7 (86%)   3/7 (43%) Titanate (600 μl) (50 μg/cm.sup.2) + coating 1 Silver 2 2 10.sup.5 cfu 10/11 (91%)    7/11 (64%) Titanate (600 μl) (100 μg/cm.sup.2) + coating 2

Influence of Heat Treatment on Elution Behaviour of Silver Titanate

[0256] Silver treated titanium parts prepared as described above in relation to test parts used in the rabbit infection study were heat treated at 280° C. for two (2) hours, resulting in a reduction in rate of elution of silver ions compared to the non-heat-treated parts. This is shown in FIG. 13. At 19 days, 96% of the silver was eluted from the silver titanate treated pins, whereas, in contrast, only 64% of the silver was eluted from the heat-treated pins after 25 days, as also shown in FIG. 13.

[0257] In a further experiment, silver treated titanium parts prepared as described above in relation to the heat treatment studies carried out on the non-coated silver titanate test coupons were subject to a two (2) hour 280° C. heat treatment prior to polymer coating. The heat treatment had a significant effect on the in vitro elution kinetics, with only 39% of the silver eluted after 53 days compared to 79% for the non-heat-treated samples, as shown in FIG. 14. The slower elution rate associated with the heat-treated samples is believed to be due to a combination of microstructural changes in the titanate structure, combined with changes in the silver nano-particulate chemistry. Moreover, the heat-treated pins were photographed after elution and found to possess a uniform dark colour, thereby confirming that a significant quantity of the silver was retained within the titanate structure, as shown in FIG. 14.

Protection of the Polymer Coated Titanate from Abrasive Forces Using Design Features and/or Bushings

[0258] The polymeric coating provides some level of lubricity to the implant during insertion into the bone canal. Equally, the thickness of the titanate and polymer coating layers may be minimized to approximately 1 and 3 μm respectively, which can help to reduce the risk of damage from mechanical abrasion during insertion via compression and torsional loading. Although these designs provide some level of protection to the antimicrobial coating during insertion into the bone canal or on the threaded portion of the implant during screw insertion, there is still a need for implementing further design features to mitigate this risk.

[0259] For example, as shown in FIGS. 15a and 15b, the use of polymeric bushings 102 to reduce metal on metal contact through screw holes 104 in the distal and proximal regions of the nail 106. In such a manner, the screw contacts the bushing, not the nail, thereby reducing the risk of abrasion of the antimicrobial coating.

[0260] Alternatively, or additionally, the use of flutes or dovetails positioned along the length of the nail are also options for reducing the amount of contact points between the antimicrobial coating and the internal surfaces of the bone canal. An embodiment showing such features is shown in FIGS. 16a and 16b (the latter figure being a cross sectional view of the former), in which longitudinal channels 108 along the external surface of the nail are shown. Such surface features can be achieved using standard CNC machining processing or sculpture milling, for example.

[0261] Alternatively, or additionally, the cross-sectional geometry of the nail can be altered from a circular to one which provides additional protection to two of the four surfaces during insertion into the bone canal by creating longitudinally extending recesses, which are offset from the internal surfaces of the bone canal. Example embodiments of this are show in FIG. 17 and FIG. 18 in which longitudinal recesses 110 (two and four respectively) extend along the length of the implant 112.

[0262] Attention is directed to all papers and documents which are filed concurrently herewith or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference in their entirety.

[0263] All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

[0264] Each feature disclosed in this specification (including any accompanying claims, abstract and drawings) may be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

[0265] The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.