WO2005072785A1

WO2005072785A1 - Highly porous 3 dimensional biocompatible implant structure

Info

Publication number: WO2005072785A1
Application number: PCT/NL2005/000050
Authority: WO
Inventors: Shihong Li
Original assignee: Cam Implants B.V.
Priority date: 2004-01-30
Filing date: 2005-01-24
Publication date: 2005-08-11

Abstract

The invention relates to a novel highly porous three-dimensional biocompatible implant structure and a process for the manufacture thereof. The porous biocompatible implant structure of the present invention is virtually free of knots and welding points and exhibits an exceptionally high mechanical strength. The invention provides a process for producing the aforementioned biocompatible implant structure, said process comprising: a) providing one or more sheets of a ductile biocompatible material; b) perforating said one or more sheets to create a porosity in the range of 40-95%; c) coating said one or more perforated sheets with a biocompatible material; d) arranging said one or more coated sheets in such a way that a three-dimensional arrangement is formed in which previously non-associated parts of the one or more perforated sheets are in direct contact; e) sintering the arrangement of one or more coated sheets under high vacuum.

Description

HIGHLY POROUS 3 DIMENSIONAL BIOCOMPATIBLE IMPLANT STRUCTURE

Technical field The present invention relates to a process for producing a 3 dimensional biocompatible, porous implant structure for biomedical applications, particularly useful as a component of prostheses.

Background art Pure titanium and titanium alloys which are considered the best biocompatible metallic implant materials are applied as temporary or permanent implants and prostheses in traumatology, orthopedics and dental surgery. From macroscopic geometric viewpoint, they can be categorized into three groups (1) dense implants; (2) macroporous implants; (3) porous surface layer (coating) on dense implants. Most implants or devices are made in dense form, for example, the hip stem for hip joint replacement. There are few reports concerning the use of bulk macroporous implants made of Ti or a Ti alloy. In contrast, many patents and , publications are concerned with the use of a porous coating on dense substrates, e.g. a hip stem or acetabular cup. The need for providing such a porous surface on implants can be explained as follows: taking the hip stem as an example, during implantation, the hip stem can be fixed in position with cement (e.g. PMMA) or without any cement: e.g. cementless hip prosthesis, which enables the prosthetic components to be fixed directly in the osseous bed. A mechanically stable anchorage must be achieved in the prosthesis/bone interface during the first postoperative weeks to ensure the permanent osseointegration of the implant. The secondary fixation of the prosthesis results through the in- and ongrowth of new bone on the surface of the implant. Two kinds of surfaces can be distinguished: bone ingrowth and bone ongrowth surfaces. Bone ingrowth surfaces are characterized by an open porous structure, through which the bone can grow into the structure. This type of surface is also known as "porous coating". Studies have shown that a pore size of 100-400 μm and a porosity volume of 30-50% are most suitable. A bone ongrowth surface is macro- micro-structured by means of suitable process, so that the bone can grow onto the surface. These surfaces are rough, with arithmetical average roughness (Ra) being usually between 4 and 15 μm. The current invention is based on two existing techniques: (1) lamination, i.e. building a 3D structure from 2D sheets or layers; (2) Powder Metallurgy (P/M), this is the technology and art of producing metal powders and of the use of metal powders for the production of massive materials and shaped objects. Thus, the relevant prior art can be divided in two groups: (1) relevant to the P/M technique used and (2) relevant with regard to the lamination method. In the following paragraphs the most relevant prior art will be discussed.

(1) Prior art relevant to producing porous objects, especially titanium, through P/M technique (0D → 3D; making 3D constructs from 0D powder) Reticulated polyurethane foam is a popular template to start with for producing reticulated titanium foam, especially for titanium foam with very high porosity, e.g. higher than 90%. Firstly, titanium powder is used to prepare a suspension/slurry with low viscosity. Subsequently, different routes can be used:

• a positive replication [Ref.l, 2]: Ti slurry is coated onto the PU foam, drying and sintering is performed to obtain a porous Ti foam; • few researchers have used negative-negative replication [Ref. 3] or investment casting; and

• one company [Ref 4] uses electrolytic deposition. Another common P/M technique for making porous Ti is to mix Ti powder with a pore-maker, normally a compound which can be removed under heating, like urea, sodium bicarbonate, PMMA beads etc. [Ref 3,5] If the organic pore-maker has also functions as a foaming agent, another group of P/M methods can be used to produce porous Ti. [Ref.6]. There exists a variation of the method employing Ti powder plus organic pore-maker, wherein an extrusion technique is used to better control the final porous structure [Ref 7]: rods consisting of a shell (Ti powder + binder) and a core (organic filler) are co-extruded, chopped, and re-packed or re-extruded again. Finally, all the organic components are removed through pyrolysis and the constructs are sintered. The pores in porous Ti can be created using organic pore-maker, as described above, or using a gas [Ref 8]: argon gas is entrapped in a pack of Ti powder under high pressure, following which the escaping argon will generate pores when the powder is heated to a temperature at which Ti becomes superplastic. Porous Ti can also be made in a rather simple way: Ti beads (solid or hollow) are packed and sintered [Ref 9], this technique was widely studied and applied as a porous coating on hip stems. Porous Ti can be made from another mature technique: vacuum plasma spraying coating. After a layer of Ti coating has been produced in this way, porous Ti is obtained by simply cutting it from the substrate. [Ref 10] Three-dimensional porous Ti can also be produced from one-dimensional Ti fibre [Ref 11], although this technique is not P/M and is less relevant to the current invention. The P/M techniques described above start from titanium powder. Therefore they all face a common technical challenge: to prevent the formation of so-called "alpha-case". In other words, to prevent the reaction between Ti powder and certain elements, notably C, N, and O, contained in air and organic components employed in the process. Oxygen in particular has a high affinity to Ti. The reason for wanting to avoid the formation of alpha- case is that an alpha-case layer is detrimental to the overall mechanical performance and is viewed as a problem by regulatory authorities. As a result the content of organic components, e.g. pore-maker or foaming agent or PU foam, must be very low, e.g. less than 2 wt.% of the total weight of the manufactured construct, or they must be removed completely at temperatures below 200 °C.

(2) Prior art relevant to producing porous objects, especially titanium, through lamination technique, in other words, 3D constructs out of 2D sheets or equivalents (2D → 3D; making 3D constructs from 2D sheets or equivalents) The most popular method of manufacturing 3D porous structures from 2D mesh has been used widely and has been applied in commercial products. For example, the fibre mesh from Zimmer USA and the mesh structure from Sulzer Orthopedics, Switzerlands [Ref 3]. EP 0677297 describes an implant material comprising as a base material a biocompatible bulk structure of a 3D woven or knitted fabric of organic fibres or a composite fabric thereof. US4636219 describes a process for producing a biocompatible mesh screen structure that can be bonded to a prosthetic substrate. Said process comprises producing a stack of 4-8 layers of mesh from titanium or alloys thereof, particularly Ti6A14V, heating the stack at a temperature ranging from 1650-1725°F and a pressure of 130-1500 psi for 12-24 hours. Each layer of the structure is biased with an angle of 45 degrees with respect to its neighbouring layers. The structure obtained can be bound to the body of a prosthesis by any welding technique known per se. French patent application 8713062 (publication number 2620623) describes a porous structure for bone repair consisting of at least 2 layers of a woven material from a metal which can be welded. The structure can be applied onto a prosthesis. EP0621018 describes a prosthesis for the replacement of hard tissues of human bones and joints, comprising a porous laminate component of biocompatible sheets with a thickness of less than 150 microns having a plurality of perforations with a diameter ranging from 100- 400 micrometer, communicating with each other in the direction of the thickness. The techniques described above share two common features: (1) the basic structural units are metal mesh, fibrous material, grids or screen etc (2) those units are bonded together through either diffusion bonding or spot welding. Therefore, the final constructs exhibit certain disadvantage like too many joints between those fibres, such joints being detrimental to the mechanical strength and especially to the fatigue strength of the constructs.

Summary of the invention A principal object of the present invention is the production of a biocompatible 3D porous metallic structure with an improved mechanical performance, and preferably a rough surface, that is suitable for osteointegration. Still another object of the present invention is a 3D porous structure produced from a stack of metal sheets with either a flattened or raised/relief pattern. If the raised/relief pattern sheets are used, the perforated sheets exhibit a slight 3D configuration even before stacking of the 2D sheets. A further object of the present invention is a process for producing the said 3D structure. In its most general form the process involves the application of powder metallurgy techniques (P/M) combined with lamination techniques. Finally, the present invention involves the use of said 3D structures for the production of a range of prosthetic devices for replacement, reconstruction and attachment to the skeletal system of humans and animals. Detailed description of the invention One aspect of the invention relates to process for producing a highly porous three- dimensional biocompatible implant structure, comprising: a) providing one or more sheets of a ductile biocompatible material; b) perforating said one or more sheets to create a porosity in the range of 40-95%, preferably in the range of 40-90%; c) coating said one or more perforated sheets with a biocompatible material; d) arranging said one or more coated sheets in such a way that a three-dimensional arrangement is formed in which previously non-associated parts of the one or more perforated sheets are in direct contact; e) sintering the arrangement of one or more coated sheets under high vacuum to obtain a highly porous three-dimensional structure with high mechanical strength, which porous three-dimensional structure is virtually free of knots and welding points. Here the terminology "previously non-associated parts" is used to make clear that the parts of the one or more sheets that are brought into direct contact during step (d) are either located on different sheets or they are located on the same sheet, but not in adjacent positions. For the production of the 3D implant structure according to the invention sheets are produced from a biocompatible material. Biocompatible materials are well known in the art and are described and defined in e.g. D.F. Williams "Progress in biomaterial engineering, 4 definitions in Biomaterials" 1987 Elsevier. Various ductile materials can be used in the present invention such as metals including titanium, titanium alloys, cobalt, cobalt alloys, tantalum and its alloys, niobium and its alloys, zirconium and its alloys or organic polymers, preferably a copolymer from polybutylene terephthalate and polyethylene glycol terephthalate. We prefer to use the above mentioned metals and particularly titanium, tantalum or alloys thereof and particularly Ti6A14V. According to the present invention sheets of the above biocompatible metals are produced according to processes known per se. The sheets are subsequently perforated by punching, etching or any other suitable methods known in the art. The perforated sheets can be made to have a flattened or raised (relief) pattern. The latter can be achieved, for instance, if an additional off-plane shear load is applied during the perforation process. The perforation is carried out to such an extent that a porosity of about 40-95%, preferably of 40-90% is achieved. The pattern and density of perforation holes and their shapes (square, rectangular, round) can be selected as required. For the purpose of biomedical application, the sheets of the present invention preferably have a thickness in the range of 100-1000 μm, more preferably in the range of 150- 800 μm. According to a preferred embodiment, perforated sheets are subsequently coated by contacting them with a powder or a suspension, preferably an aqueous suspension, containing said biocompatible materials. Said suspension preferably contains a powder consisting of one of the biocompatible metals mentioned above and most preferably a powder consisting of titanium or tantalum. The suspension suitably contain minor amounts of additives including a suspension agent, preferably an ammonium salt of an acrylate polymer, and a thickening agent such as carboxymethylcellulose. The amount of metal powder suspended in the aforementioned suspension advantageously is kept within the range of 40-80 wt.%, preferably 50-70 wt.%, the remainder comprising water and additives. The organic additives are typically contained in the suspension in a concentration of less than 2 wt.%, preferably of less than 1 wt.% and most preferably of less than 0.5 wt.%. Alternatively, the perforated sheets may be coated by applying adhesive to the perforated sheets, e.g. by means of an aerosol spray, followed by contacting the sheets with a biocompatible material in powder form, e.g. by immersing the coated sheets in such a dry powder. This methodology is particularly useful if the average diameter of the perforations is relatively small, e.g. less than 500 μm as it helps to avoid plugging of the perforations. Suitable adhesives are known in the art. Particularly suitable adhesives include adhesives comprising styrene-butadiene rubber with a flashpoint of less than 0 °C and a viscosity below 1 Pa at 20 °C. In the present process typically 2-8 sheets are stacked by lamination (with or without slight compression). The sheets may be stacked in various orientations or alignment angles of one sheet with respect to the next one. If the sheets have been coated with a suspension, said sheets are advantageously dried before sintering, e.g. by means of air drying. According to an alternative embodiment of the invention one or more coated sheets are rolled up so as to obtain a cylindrical construct. Naturally, it is also possible to convert the coated sheet in any other desirable shape or contour. The sintering conditions to be employed during step (e) are dependent on the material used. In case the preferred biocompatible metals are used, i.e. titanium, tantalum or alloys thereof, the preferred sintering temperature is in the range of 1100 °C to 2000 °C. Heating is carried out at in high vacuum preferably at a pressure of less than 10^"5 millibar. Typically, sintering conditions are maintained for at least 1 hour and preferably during 2-5 hours. Sintering is suitably carried out in a vacuum furnace, preferably under an atmosphere of helium or argon. In accordance with a preferred embodiment, the sintered structure is subjected to a chemical treatment in order to modify its surface properties, e.g. by applying an alkali treatment (such as potassium or sodium hydroxide). A primary objective of such chemical treatment is to increase surface roughness. An average surface roughness ranging from 5 to 12 μm is achievable. An average surface roughness in the range of 8 to 10 μm is particularly preferred since it enhances bone ongrowth. The 3D, biocompatible implant structures according to the invention and obtainable from the process hereinbefore described and defined, have a highly porous structure predominantly consisting of interconnected open pores of suitable size distribution and are virtually free from knots and welding points, resulting in an improved mechanical strength, as evidenced by a compressive strength that exceeds lOMPa. The compressive strength can be determined by applying the following testing conditions: block sample with cross-sectional area of 10x10 mm and the crosshead speed being 1 mm/minute, tested with a mechanical testing machine LR50K, number 01/1934 from LLOYD Instruments (UK). In another preferred embodiment, the 3D structures according to the invention have their complete surface roughened by being coated with a finely divided metal powder, such as titanium powder, as evidenced by a roughness ranging from 5-12 μm, preferably 8-10 μm. The latter roughness parameter (Ra) can suitably be measured with a laser profilermeter from UBM Messtechnik GmbH, Germany. The roughness of perforated Ti-sheets was found to be around 0.8 μm (averaged Ra), whereas after lamination, P/M processing and coating with a layer of Ti powder this roughness changed to 8.5 μm (averaged Ra). The 3D structures according to the invention suitably comprise stacks of sheets with a thickness from 100-1000 microns, preferably 150-800 microns, said sheets being made from a ductile material, preferably from a metal as defined herein before. In accordance with the invention these sheets have been laminated, preferably under slight pressure, sintered and bonded through powder metallurgy techniques. The porosity of the structure ranges from 40- 95%, preferably from 40-90%. The present invention also encompasses the use of the new 3D structures as herein before defined for the production of implants and prosthesis for osteosynthesis in which they are fixed in a known way, e.g. using the methodology described in EU0621018. The invention will now be illustrated in the following examples. Example 1.

Commercially available titanium sheets with a thickness of about 510 micrometer were purchased. Holes were punched from both the top and bottom sides of the sheets while applying an off-plane shear load in order to obtain a raised/relief pattern of holes with an average diameter of about 1000 microns. The perforated sheets were passed through a roller to achieve a flattened pattern.

Fig. 1 Optical micrograph showing the perforated Ti sheets used in this example

A suspension of titanium powder with the following composition was produced:

The sheets were dipped in the suspension, stacked by lamination with a biased angle of 45 degrees and air-dried .The sheets contained less than 0.3% organic additives stemming from the coating suspension. The stacks were brought in a vacuum furnace where sintering at 1300°C under a pressure of lower than about 10^"5 millibar under an argon atmosphere for 3 hours. The structure obtained was rough on all surfaces, average roughness being 8 μm. The measured mechanical strength, namely compressive strength, of the structure was as high as 49 MPa. Under the microscope the structure displayed was highly porous with a high degree of connection between open pores. Optical micrographs (Fig 2b) show the structure obtained.

Fig.2 (a) Surfaces of perforated Ti sheets before P/M treatment (upper one) and after P/M treatment (lower one) (b) 3D structure from 2D perforated T sheets

Example 2 The procedure of example 1 was repeated, but this time using perforated commercially pure Ti sheets with a raised pattern. The perforated sheets had a porosity of 76% and a pore size of 1.5 x 0.5 mm, as illustrated in Fig. 3.

Fig. 3 Two sides of the perforated Ti sheets (porosity = 76%) used in this example

The obtained structure had outstanding mechanical strength (i.e. higher than 49 MPa for compressive strength measured vertically to the sheet plane direction) and under the microscope it showed the same outstanding structural properties as in Example 1. Depending on the stacking method, or the relative alignment angle of the adjacent sheets, the overall porosity and individual pore size can be varied to some extent. Example 3

The procedure of example 1 was repeated while this time perforated c.p. Ti sheets with flattened pattern were used. The perforated sheets had a porosity of 90% and pore size of 1.0 x 2.0 mm. The thickness of the sheets is 150 μm and shown in Fig.4.

Fig.4 Two sides of the perforated Ti sheets (porosity = 90%) used in this example The obtained structure had a reticulate porous structure with a very high porosity of

90%. Depending on the perforated sheets used with various porosities, stacking method, or the relative alignment angle of the adjacent sheets, the overall porosity and individual pore size can be varied to some extent.

Example 4 The procedure of example 1 was repeated while this time Ti6A14V powder is used instead of titanium powder in the suspension for coating. Since the aforementioned c.p. Ti sheets were used, the final 3D constructs comprised biphasic struts: c.p. titanium core with an outer layer of Ti6A14V as sleeves. Both the static compressive strength and dynamic fatigue strength of the composite structure exceeded those of the structures described in example 1. References 1. J.P. Li, S.H. Li, K. de Groot, and P. Layrolle, Preparation and characterization of Porous Titanium, Key Engineering Materials Vols 218-220 (2002) p51-54. 2. Commercial products information from www.astromet.com/200.htm and www.porvairfuelcells.com 3. Markus Windier, Ralf Klabunde, Titanium for Hip and Knee prostheses, from book: Titanium in Medicine, edited by D.M. Brunette, P. Tengvall, M. Textor, P. Thomsen, Springer, 2001, P726 4. Reade Advanced materials (http://www.reade.com/Products/Foam/foam-metal.html) 5. M. Bram, C. Stiller, H.P. Buchkremer, D. Stover, H. Bauer, Preparation and characterization of high-porosity titanium, stainless steel, and superalloy parts, from Metal foams and porous metal structures, edited by J. Banhart, M.F. Ashby, and N. A. Fleck, MIT Verlag (1999) P.197-202 6. Maxime Gauthier, National Research Council Canada, presentation on ASM Materials & Processes for Medical Devices Conference, Sept 8-10, Anaheim, California, USA 7. L. Tuchinskiy and R. Loutfy, Novel process for cellular materials with oriented structure, from Metal foams and porous metal structures, edited by J. Banhart, M.F. Ashby, and N.A. Fleck, MIT Verlag (1999) 8. D.C. Dunand, J. Teisen, Superpastic foaming of titanium and Ti-6A1-4V, Mat. Res.Soc. Symp. Proc. Vol. 521 1998 9. Pilliar, R.M., Overview of surface variability of metallic endosseous dental implants: textured and porous surface-structured designs. Implant Dent, 1998. 7(4): p. 305-14. 10. S. Fujibayashi, M. Neo, H. Kim, T. Kokubo, T. Nakamura, Osteoinduction of porous bioactive titanium metal, Biomaterials, 2003 11. Product from Zimmer Japan (Tokyo, Japan), scientific publication appeared at N. Murakami, N. Saito, H. Horiuchi, T. Okada, K. Nozaki, K. Takaoka, Repair of segmental defects in rabbit humeri with titanium fiber mesh chlinders containing recombinant human bone morphogenetic protein-2 (rhBMP-2) and a synthetic polymer, J. Biomed. Mater. Res. 62(2): 169-174, 2002.

Claims

1. A process for producing a highly porous three-dimensional biocompatible implant structure, comprising: a. providing one or more sheets of a ductile biocompatible material; b. perforating said one or more sheets to create a porosity in the range of 40-95%; c. coating said one or more perforated sheets with a biocompatible material; d. arranging said one or more coated sheets in such a way that a three- dimensional arrangement is formed in which previously non-associated parts of the one or more perforated sheets are in direct contact; e. sintering the arrangement of one or more coated sheets under high vacuum to obtain a highly porous three-dimensional structure with high mechanical strength, which porous three-dimensional structure is virtually free of knots and welding points.

2. Process according to claim 1, wherein step d) comprises stacking two or more coated sheets to create a three-dimensional arrangement in the form of laminate structure.

3. Process according to claim 1, wherein step d) comprises rolling up a coated sheet to create three-dimensional arrangement in the form of a cylindrical construct.

4. Process according to any one of the preceding claims, wherein the one or more perforated sheets are coated by contacting them with a powder or a suspension comprising biocompatible material, preferably the same biocompatible material of which the one or more sheets have been made.

5. Process according to claim 4, wherein the one or more perforated sheets are coated with an adhesive prior to being contacted with the powder comprising biocompatible material.

6. Process according to any one of the preceding claims, wherein the openings in the perforated sheets have a mean diameter of less than 500 μm.

7. Process according to any one of the preceding claims, wherein the ductile biocompatible material consists of a metal, an alloy of metals or an organic polymer.

8. Process according to claim 7, wherein the ductile material is selected from the group consisting of titanium, tantalum, cobalt, zirconium and alloys of these metals.

9. Process according to claim 5, wherein the ductile material consists of a polymer of polybutene terephthalate and polyethylene glycol terephthalate.

10. Process according to any one of the preceding claims, wherein perforation is carried out by etching or punching the sheets to obtain openings with an average diameter of 200- 2000 μm.

11. Process according to any one of the preceding claims, wherein the one or more sheets are perforated to produce a relief pattern by punching holes from the bottom and the top side of the sheets while applying an off-plane shear load.

12. Process according to any one of the preceding claims, wherein the perforated sheets are coated with a suspension, preferably an aqueous suspension, of a metal powder consisting of titanium, tantalum and/or Ti6A14V.

13. Process according to claim 12, wherein the solids content of the suspension is within the range of 40-80 wt.%, preferably of 50-70 wt.%.

14. Process according to claim 13, wherein the suspension additionally contains a thickening agent, preferably a thickening agent selected from the group consisting of methylcelluloses, polyethylene oxides, alginates and acrylate polymers.

15. Process according to any one of claims 12-14, wherein the suspension contains less than 2 wt.%, preferably less than 0.5 wt.% of the additives.

16. Process according to claim 1, wherein the sheets are stacked in different special orientations, preferably under light compression.

17. Process according to claim 1, wherein the ductile materials consists of metal or an alloy of metals and sintering is carried out at a temperature of 1100-2000°C.

18. Process according to any one of the preceding claims, wherein sintering is carried out at a pressure of less than 10^"5 millibar.

19. Process according to any one of the preceding claims, wherein sintering conditions are maintained for at least 1 hour, preferably for 2-5 hours.

20. A process according to any of the preceding claims, wherein the sintered three- dimensional structure is treated with an alkali solution, preferably a solution of sodium hydroxide or potassium hydroxide.

21. A three-dimensional biocompatible implant structure with a highly porous structure and a mechanical strength, expressed as compressive strength, in excess of 10 Mpa, consisting of a sintered pack of perforated sheets from a ductile biocompatible material, which perforated sheets exhibit a porosity of 40-95%, said structure being virtually free from knots or welding points.

22. Structure according to claim 21, wherein all the surfaces of the structure are rough as evidenced by an average roughness Ra of 5-12 μm, preferably 8-10 μm.

23. Structure according to claim 21 or 22, consisting of a stack of sheets made of tantalum, titanium or alloys containing one or more of these metals, the alloy Ti6A14V being preferred.

24. Structure according to any one of claims 21-23, wherein the sheets have a thickness of 100-1000 μm, preferably of 150-800 μm.

25. Three-dimensional implant structure obtainable by a process according to any one of claims 1-20.

26. Prosthesis comprising an implant structure according to any one of claims 21-25.