ADHESION PROMOTION OF ORTHOPAEDIC IMPLANTS

Abstract: A method of treating a medical implant having an exposed metallic, metal oxide or ceramic surface to enhance the adhering of acrylate cement thereto. The treatment includes coating at least a portion of the exposed surface with an alkoxy silane coupling agent having at least one polymerizable vinyl group. No further treatment is necessary for enhanced adhesion of acrylate cement to the coated surface.

Description: ADHESION PROMOπON OF ORTHOPAEDIC IMPLANTS This invention relates to the treatment of orthopaedic implant alloys to improve the adhesion to acrylate cements. In the early 1960's polymethylmethacrylate (PMMA) bone cement was first used by Manchester orthopaedic surgeon, John Charnley, to fix an artificial hip joint into the bone of the femur and the pelvis. It has since been shown that PMMA bone cement is a highly effective way of securing the artificial prostheses into the living bone and joint replacement using this technique has become a commonplace and highly successful operative procedure. The failure of an artificial joint requires a revision operation in which the prostheses is replaced. Such an operation can present technical difficulties for the orthopaedic surgeon and, because the condition of the host bone has generally deteriorated, the prognosis for revisions are generally not as good as for primary procedures. Therefore, despite the low primary failure rates, there are compelling reasons to further reduce the incidence of failure. The principal long-term mode of failure of an artificial joint is aseptic loosening. The mechanisms of aseptic loosening are not clearly understood and some debate has centred on whether the origin of this loosening is a mechanical failure of the cement-prostheses interface or an adverse biological response at the cement-bone interface. Recently, analysis of retrieved post-mortem specimens of implanted hips has given a unique insight into the early failure mechanisms implicated in the aseptic loosening of cemented femoral prostheses (Jasty et al. (1991)). The paper discloses that the mechanism of aseptic loosening is initiated with debonding at the femoral stem-cement interface. The debonding becomes associated with the production of cracks within the cement mantle surrounding the prosthesis as the cement undergoes a fatigue fracture process. The gradual accumulation of this fatigue damage weakens the cement increasing its susceptibility to gross mechanical failure and also produces paniculate cement debris which stimulates an adverse biological response at the cement-bone interface further diminishing the integrity of the fixation. The outcome of this vicious circle of deterioration is a painful and unstable joint which demands the revision of the prosthesis. U.S. 4281420 AND 4365359 disclose the use of silane coupling agents for adhesion promotion of implant alloys in a process which comprises the application of a thin layer, 0.001 to 0.002 inches, of PMMA to the alloy surface either in the presence of a silane coupling agent or after application of silane coupling agent. The PMMA layer is annealed at 80°C to 170°C, generally at 160°C, cooled slowly, and the resulting prosthetic device is then ready for use and is fixed to bone with PMMA bone cement. The present invention provides alternative method for adhesion promotion of acrylate cement to implant alloys. Therefore according to the invention there is provided a method of treating a medical implant having an exposed metallic, metal oxide or ceramic surface to enhance the adhering of acrylate cement thereto, which comprises coating at least a portion of the exposed surface with a coupling agent consisting essentially of alkoxy silane having at least one polymerizable vinyl group. As used herein the term "coating" refers to the deposition of a coating agent on the surface of the implant. It is understood that the coating may be continuous or discontinuous. Also according to the invention there is provided a method of enhancing the adhesion of acrylate cement to a metallic surface which comprises treating the metallic surface with a coupling agent which is an alkoxy-silane having at least one addition-polymerisation group and applying to the treated surface the acrylate cement, in which the acrylate cement is not annealed. The invention also provides a metallic prosthetic element comprising a surface having an outer "layer" of an alkoxy silane having at least one addition- polymerisation group, the outer layer having been cured. This "layer" may be continuous or discontinuous. It has been found that the use of a thin annealed layer of acrylate cement is unnecessary and enhanced surface adhesion of a metal surface, e.g., a prosthesis, to acrylate cement may be obtained simply by applying a surface coating of the -2- SUBSTTTUTE SHEET RULE 26) coupling agent and curing prior to application of the acrylate cement. The adhesion is increased by curing the surface coating of coupling agent by aging the exposed surface for at least 1 day, preferably 7 days prior to bonding with acrylate cement. Suitable coupling agents are those of the general formula: /( R 2 ) n (R 3 ) X — Si (OR 1 ) m in which; R 1 and R 2 independently represent alkyl groups of 1 to 3 carbon atoms, m is 2 or 3 and n is 0 or 1 such that m + n = 3 X is a bond or a p+1 valent linking group where p is an integer of 1 or more and at least one of each R 3 represents a group comprising an addition- polymerizable moiety, with the addition-polymerizable moiety being at least one, preferably three, more preferably at least five, and most preferably at least ten atoms removed from the silicon atom, and the others of R 3 may be additionally selected from alkyl, aryl, aralkyl and mixtures thereof. Each R 3 generally contains no more than 20 carbon atoms, preferably no more than 18. R 3 may optionally be substituted in available positions and/or interrupted by nitrogen, oxygen or sulphur atoms. Preferably, m = 3, n = 0 and R 1 is CH 3 or C 2 Hs and R 3 represents acrylate, methacrylate, vinyl ether or styrene-containing groups. There is no theoretical upper limit for the value of p, but values in the range 1-6 are preferred. Preferably, the linking group X provides a chain of at least 4 atoms between the polymerizable moiety and the silane group. -3- SUBSTTTUTE SHEET (RULE 26) Preferred silanes are selected from: A general method of implanting a metallic surgical prosthesis in accordance with the invention comprises the steps of; (a) forming a thin layer, e.g., (up to 1.0 microns) on the surface of the prosthesis of an alkoxysilane coupling agent bearing one or more addition- polymerisation groups; and (b) curing the coupling agent. SUBSTITUTE SHEET (RULE 25) At the time of surgery an acrylate based cement may be used in order to bond the prosthetic element in the desired location. Preferably the prosthesis is stored at ambient temperature for at least one day (i.e., about 24 hours), more preferably at least one week, prior to implantation to allow curing. Preferably, the coating of step (a) should be carried out by contacting, particularly dipping the prosthesis in a dilute alcoholic solution of the silane. The coating may be uniform or applied pattern-wise. The concentration range should be 0.001 to 10%, w/v and the residence time 1 minute to 2 hours. A typical treatment comprises 10 minutes residence in a 1% w/v solution. The silane treatment may be carried out in the presence of ultrasound, e.g., in a conventional ultrasound cleaning bath, in order to promote interaction between the silane and the metal surface. After treatment, the prosthetic element is rinsed in clean solvent and dried and cured at elevated temperatures, preferably above 50°C. The final heat treatment to cure is typically 120°C for 15 minutes. The higher the temperature, generally the shorter the time required. Preferably, the prosthesis is cleaned prior to step (a) by ultrasonic treatment in ethanol or similar cleaning solvents, e.g., for 1 minute to 2 hours, typically 10 minutes. The invention will now be illustrated by the following Examples in which all experiments were performed with metal alloy lap-shear specimens treated in an identical manner to prepared metal implants. Samples were machined to flat oblong specimens (dimensions 51mm x 4mm) to enable lap-shear experiments to be performed. The following metal alloys were used: Ti alloy - (Ti6A14V) CoCr Mo alloy - (27% Cr, 5% Mo, 68% Co) stainless steel - (High N 2 content.British Standard 7252 pt 9 1990) Prior to treatment each sample was cleaned in ethanol for 10 minutes under ultrasonication. Once degreased, samples were rinsed in a clean solution of ethanol and dried at room temperature. At this stage same samples were surface treated with coupling agent. Treatment with coupling agent was performed in an ultrasonic bath using the required concentration of coupling agent in ethanol or methanol. After rinsing the treated sample in clean alcohol and drying at room temperature, samples were placed in an oven at 105-120°C for 15 minutes. Treated samples were then ready for application of PMMA cement. PMMA cement was applied in order to demonstrate the superior adhesion achieved by the present invention. The cement used was PMMA and activator with MMA monomer. Two samples were overlapped by 1cm and bonded together with the PMMA cement keeping the cement thickness between samples constant (approximately 0.5mm). After curing for 1 hour at room temperature, the samples were put into an oven at 80°C for 90 minutes to ensure uniformity of cure among samples. Lap-shear specimens under test were fitted between the lower clamp and the moving cross-head of an Instron tester. The cross-head on the Instron (model 1026) was set to drive upwards at 5mm/min, using a 500kg load cell. The maximum load at failure was converted to an interface shear stress (ISS), representing the interface shear strength, using the formula ISS=P/A, where P is the maximum load in Kg and A is the interfacial contact area calculated from examination of each of the samples after breakage in mm 2 . Example 1 A series of Ti alloy samples were tested for interface shear strength; Three types of samples were employed. a) untreated sample (control) b) sample surface treated with a 1% solution of methacryloxypropyl trimethoxy silane. c) sample surface treated with a 1% solution of aminopropyltriethoxy silane. -6- BSTTTUTE SHEET RULE 26 The following Table reports the mean ISS values (Kg/mm 2 ). Type of Sample No. Samples Mean (Kg/mm 2 ) Standard Deviation Tested Untreated 34 0.96 0.22 Treated with 1% 14 1.56 0.25 Acrylate Silane Treated with 1% 9 1.08 0.15 Amino Silane The data presented in the Table indicates that the samples treated with acrylate functional silane coupling agent exhibit a higher stress at yield presumably due to formation of covalent bonds at the metal - cement interface. Samples treated with amino silane gave similar values to untreated specimens indicating that the choice of functional group on the silane coupling agent is critical. This data suggests that not all of the silane materials listed in US 4365359 provide for improved adhesion using the method of Example 1. Example 2 The following types of sample were prepared using Ti alloy: (1) untreated control, (2) sample surface treated with 1% solution of methacryloxypropyl trimethoxy silane in accordance with the invention, (3) sample surface coated with a thin layer (less than 0.1mm) of PMMA without use of coupling agent, as disclosed in Stone et al., J. of Bone and Joint Surgery, 71B, (1989), 217, (4) sample surface coated with a thin layer of PMMA without use of coupling agent, the PMMA layer being heated first at 80°C for two hours to enable the cement to cure and then at 160°C for a further twenty-four hours to form a glassy layer (annealing) as disclosed in US 4281420, -7- SUBSTHUTE SHEET (RULE 26) (5) sample surface treated with 1% solution of methacryloxypropyl trimethoxy silane (MA) as in sample (2) to which was applied a thin layer of PMMA which was cured and annealed as in sample (4), as disclosed in US 4365359, (6) sample treated as sample (5) using aminopropyltriethoxy silane in place of MA. Lap-shear tests were conducted on each type of sample which were bonded with the PMMA bone cement described above. The results are reported in the following Table. Sample Type Mean Stress At Yield Standard Deviation 1 0.96 0.22 2 1.56 0.25 3 0.77 0.13 4 1.11 0.27 5 1.38 0.30 6 1.35 0.11 The data presented in the Table shows that the method of the invention (Sample 2) which applies the PMMA cement directly onto a silane coated metal alloy is superior to the two prior art methods (Samples 3 to 6). Note that, if the applied thin PMMA layer is not annealed (Sample 3) its performance is poor even compared to the untreated control. Example 3 A series of experiments were conducted to prove the stability of the silane coating once applied to the prosthetic element. Ti alloy specimens were surface treated with 1% methacrylate silane as in Example 1 and placed in a desiccator, open to a normal laboratory environment, but with the lid in place to prevent the samples accumulating dust. Samples were -8- SUBSTITUTE SHEET RULE 25) removed on a weekly basis and lap shear tests conducted as described above. The results are in the following Table. Storage Time (weeks) Sample Mean (Kg/mm 2 ) Standard Deviation Control Untreated 0.96 0.22 0 1.56 0.25 1 2.27 0.29 2 2.12 0.13 3 2.27 0.20 4 2.48 0.18 The results clearly show that storage of surface treated samples is not detrimental to the performance of the silane coupling agent. In fact, the adhesive strength of the constructed lap-shear specimens appear to increase when the specimens have been left coated for one week under normal (dust free) laboratory conditions. Example 4 Lap-shear tests were conducted on different metal samples untreated and surface treated with methacryloxypropyl trimethoxysilane as in Example 1. The results are reported in the following Table. Sample No. Samples Mean (Kg/mm 2 ) Standard Tested Deviation Untreated CoCr Mo 8 1.40. 0.25 Treated CoCr Mo 8 2.05 0.31 Untreated Stainless Steel 8 1.24 0.13 Treated Stainless Steel 8 2.35 0.30 -9- SUBSTTTUTE SHEET (RULE 26) The results clearly demonstrate that an improvement in adhesion is achievable with different metal alloy substrates. Example 5 Two new silane materials were synthesised. Silane (A) is designed with a longer organic chain between the silane end group and acrylate functionality, and Silane (B) contains three acrylate groups, rather than the single group present in MA used in the previous Examples. Synthesis of Silane (A) One equivalent of 2-hydroxy ethyl methacrylate was added to isocyanatopropyltriethoxy silane and the mixture was cooled in an ice bath. An infra-red spectrum was taken and the size of the peak due to the isocyanate function (approximately 2270 cm '1 ) was noted. Two drops of dibutyltindilaurate were added to act as a catalyst. The mixture was then left at room temperature for about 48 hours when another spectrum was taken. The reaction was judged to be complete when the isocyanate peak had disappeared. (m.w.=377) Synthesis of Silane (B) Two equivalents of pentaerythritol triacrylate (tech. grade, approximately 36% triacrylate present) in dichloromethane was added to one equivalent of isocyanato propyl triethoxy silane. The mixture was chilled and monitored for isocyanate peak presence in IR (as above). Dibutyl tin dilaurate (two drops) was added and the reaction was left for 48 hours, until the isocyanate peak in the JR. had disappeared. A little hydroquinone was added to the mixture to prevent product polymerisation. The remaining solvent was removed under vacuum immediately prior to use. (m.w.=559) Lap-shear specimens on Ti alloy constructed after surface treatment with 1% Silane (A) and 1% Silane (B) coupling agents were evaluated for maximum stress and yield using the test method described above. The results are reported in the following Table together with previous results obtained from both untreated Ti alloy and Ti alloy treated with 1% MA for comparison. Sample No. Samples Mean Stress At Standard Yield Deviation Untreated control 34 0.96 0.22 1% Acrylate Silane 14 1.56 0.25 1% Silane (A) 15 1.70 0.21 1% Silane (B) 6 1.74 0.41 The data presented shows that both Silanes (A) and (B) offer improved adhesion of PMMA cement to the metal alloy.

Claims: CLAIMS: 1. A method of treating a medical implant having an exposed metallic, metal oxide or ceramic surface to enhance the adhering of acrylate cement thereto, which comprises coating at least a portion of the exposed surface with a coupling agent consisting essentially of an alkoxy silane having at least one polymerizable vinyl group. 2. A method as claimed in Claim 1 in which the coupling agent has the general formula: in which; R l and R 2 independently represent alkyl groups of 1 to 3 carbon atoms, m is 2 or 3 and n is 0 or 1 such that m + n = 3 X is a bond or a p+1 valent linking group where p is an integer of 1 or more and at least one R 3 represents a group comprising an addition- polymerizable moiety wherein the addition-polymerizable moiety is at least one atom removed from the silicon atom, and the others of R 3 may be additionally selected from alkyl, aryl, arakyl and mixtures thereof, wherein each R 3 comprises between 1 and 20 carbon atoms. 3. A method as claimed in Claim 2 in which m = 3, n = 0 and R 1 is CH 3 or C 2 H 5 . -12- SUBSTΓTUTE SHEET (RULE 25) 4. A method as claimed in Claim 2 or Claim 3 in which R represents acrylate, methacrylate, vinyl ether or styrene-containing groups. 5. A method as claimed in any preceding Claim in which the coupling agent is selected from: and vinyltris(beta-methoxyethyl) silane. 6. A method as claimed in any preceding Claim in which the coupling agent is in the form of a layer having a thickness of approximately 1 micron. -13- SUBSTTTUTE SHEET (RULE 25) 7. A method as claimed in any preceding Claim in which the coupling agent is applied by contacting the surface with an alcoholic solution of the coupling agent having a concentration of from 0.001 to 10% w/v. 8. A method as claimed in Claim 7 in which the coupling agent is applied by dipping in solution under ultrasonication. 9. A method as claimed in any preceding Claim in which the metallic surface is cleaned in ethanol under ultrasonication prior to application of coupling agent. 10. A method as claimed in any preceding Claim in which the metallic surface is washed with solvent after application of the coupling agent. 11. A method as claimed in any preceding Claim in which the coupling agent is cured by heating to a temperature above 50°C for at least one minute after application to the metal surface. 12. A method as claimed in Claim 11 in which the coupling agent is cured by heating to a temperature of about 120°C for about 15 minutes. 13. A method of enhancing the adhesion of acrylate cement to an implant which comprises treating the implant by the method of Claim 1 and applying to the treated surface the acrylate cement, in which the acrylate cement is not exposed to temperatures in excess of 80°C. 14. A medical implant having an exposed metallic, metal oxide or ceramic surface wherein at least part of said surface bears a cured coating of a coupling agent comprising an alkoxy silane having at least one polymerizable vinyl group, said surface being free from acrylate cement. 15. A method as claimed in Claim 14 in which said coated surface has been exposed for at least 24 hours. ■ 14- SUBSTTTUTE SHEET (RULE 26) 16. A medical implant as claimed in Claim 14 in which the coupling agent has the general formula: ( R3 ) - X ~ SI \ P ^(OR ) m in which; R 1 and R 2 independently represent alkyl groups of 1 to 3 carbon atoms, m is 2 or 3 and n is 0 or 1 such that m + n = 3 X is a bond or a p+1 valent linking group where p is an integer of 1 or more and at least one R 3 represents a group comprising an addition- polymerizable moiety wherein the addition-polymerizable moiety is at least one atom removed from the silicon atom, and the others of R 3 may be additionally selected from alkyl, aryl, aralkyl and mixtures thereof, wherein each R 3 comprises between 1 and 20 carbon atoms. ■ 15- SUBSTTTUTE SHEET (RULE 25)

Inventors: BOTTOMLEY WILLIAM E, NORMAN COLIN F, SWAN MICHEAL D, BOTTOMLEY, WILLIAM, E., NORMAN, COLIN, F., SWAN, MICHEAL, D.
Applicants: BOTTOMLEY WILLIAM E, MINNESOTA MINING & MFG, NORMAN COLIN F, SWAN MICHEAL D, BOTTOMLEY, WILLIAM, E., MINNESOTA MINING AND MANUFACTURING COMPANY, NORMAN, COLIN, F., SWAN, MICHEAL, D.
Application year: 1996
Main classification: A61L27
IPC codes: A61L26, A61L27, C07F7